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Does Abatacept and Doconexent interact?

•Drug A: Abatacept •Drug B: Doconexent •Severity: MODERATE •Description: The metabolism of Doconexent can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used as a high-docosahexaenoic acid (DHA) oral supplement. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): DHA in the central nervous system is found in the phospholipid bilayers where it modulates the physical environment and increase the free volume within the membrane bilayer. It influences the G-protein coupled receptor activity and affects transmembrane transport and cell interaction with the exterior world. It is also reported to promote apoptosis, neuronal differentiation and ion channel activity. Like other polyunsaturated fatty acids, DHA acts as a ligand at PPARs that plays an anti-inflammatory effect and regulate inflammatory gene expression and NFκB activation. DHA also gives rise to resolvins and related compounds (e.g., protectins) through pathways involving cyclooxygenase and lipoxygenase enzymes to resolve the inflammatory responses. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): DHA and its conversion to other lipid signalling moleccules compete with the arachidonic acid cascade from endogenous phospholipids and shift the inflammatory state to being more anti-inflammatory. DHA inhibits endotoxin-stimulated production of IL-6 and IL-8 in human endothelial cells. Derivatives of DHA are anti-inflammatory lipid mediators. Lipid mediators resolvin D1 and protectin D1 all inhibit transendothelial migration of neutrophils, so preventing neutrophilic infiltration at sites of inflammation, resolvin D1 inhibits IL-1β production, and protectin D1 inhibits TNF and IL-1β production. Monoxydroxy derivative of DHA converted by LOX inhibit thromboxane-induced platelet aggregation. DHA supplementation has also shown to reduce the levels of serum C-reactive protein (CRP) and other circulating markers of inflammation such as neutrophils in hypertriglyceridemic men. DHA acts as a ligand at peroxisome proliferator-activated receptor (PPAR) gamma and alpha that regulate lipid signalling molecule-mediated transduction pathways and modulate inflammation. As a natural ligand, DHA induces a protective effect in retinal tissues by activating retinoid x receptors and subsequent ERK/MAPK signaling pathway in photoreceptors to promote their survival and differentiation, stimulating the expression of antiapoptotic proteins such as Bcl-2 and preserving mitochondrial membrane potential. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Like other omega-3 fatty acids, DHA is hydrolyzed from the intestines and delivered through the lymphatic circulation. Plasma DHA concentrations increase in a dose-dependent and saturable manner. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): DHA is the most abundant n−3 fatty acid in membranes and is present in all organs. It is also the most variable among organs and is particularly abundant in neural tissue, such as brain and retina, where it is several hundred-fold more abundant than EPA. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others. It is converted to 17-hydroperoxy-DHA derivatives via COX-2 and 15-LOX and 5-LOX activity. These derivatives are further converted into D-series resolvins and protectins with potent anti-inflammatory potential and potent neuroprotective effect. DHA may also be metabolized to 19,20-epoxydocosapentaenoic acids (EDPs) and isomers via CYP2C9 activity. Epoxy metabolites are reported to mediate anti-tumor activity by inhibiting angiogenesis, tumor growth, and metastasis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Approximately 20 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral LD50 value in rats is 7,060 mg/kg and 3,450 mg/kg in mouse. Adverse effects include anemia, cough, CNS depression, drowsiness, headache, heart damage, lassitude (weakness, exhaustion), liver damage, narcosis, reproductive effects and teratogenic effects. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Animi-3 With Vitamin D, Citranatal Harmony •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 22:6(n-3) all-cis-DHA cervonic acid Doconexent Docosahexaenoic acid Docosahexanoic Acid •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doconexent is an omega 3 fatty acid used in a variety of nutritional supplements to support central nervous system and cardiovascular health.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Doconexent interact? Information: •Drug A: Abatacept •Drug B: Doconexent •Severity: MODERATE •Description: The metabolism of Doconexent can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used as a high-docosahexaenoic acid (DHA) oral supplement. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): DHA in the central nervous system is found in the phospholipid bilayers where it modulates the physical environment and increase the free volume within the membrane bilayer. It influences the G-protein coupled receptor activity and affects transmembrane transport and cell interaction with the exterior world. It is also reported to promote apoptosis, neuronal differentiation and ion channel activity. Like other polyunsaturated fatty acids, DHA acts as a ligand at PPARs that plays an anti-inflammatory effect and regulate inflammatory gene expression and NFκB activation. DHA also gives rise to resolvins and related compounds (e.g., protectins) through pathways involving cyclooxygenase and lipoxygenase enzymes to resolve the inflammatory responses. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): DHA and its conversion to other lipid signalling moleccules compete with the arachidonic acid cascade from endogenous phospholipids and shift the inflammatory state to being more anti-inflammatory. DHA inhibits endotoxin-stimulated production of IL-6 and IL-8 in human endothelial cells. Derivatives of DHA are anti-inflammatory lipid mediators. Lipid mediators resolvin D1 and protectin D1 all inhibit transendothelial migration of neutrophils, so preventing neutrophilic infiltration at sites of inflammation, resolvin D1 inhibits IL-1β production, and protectin D1 inhibits TNF and IL-1β production. Monoxydroxy derivative of DHA converted by LOX inhibit thromboxane-induced platelet aggregation. DHA supplementation has also shown to reduce the levels of serum C-reactive protein (CRP) and other circulating markers of inflammation such as neutrophils in hypertriglyceridemic men. DHA acts as a ligand at peroxisome proliferator-activated receptor (PPAR) gamma and alpha that regulate lipid signalling molecule-mediated transduction pathways and modulate inflammation. As a natural ligand, DHA induces a protective effect in retinal tissues by activating retinoid x receptors and subsequent ERK/MAPK signaling pathway in photoreceptors to promote their survival and differentiation, stimulating the expression of antiapoptotic proteins such as Bcl-2 and preserving mitochondrial membrane potential. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Like other omega-3 fatty acids, DHA is hydrolyzed from the intestines and delivered through the lymphatic circulation. Plasma DHA concentrations increase in a dose-dependent and saturable manner. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): DHA is the most abundant n−3 fatty acid in membranes and is present in all organs. It is also the most variable among organs and is particularly abundant in neural tissue, such as brain and retina, where it is several hundred-fold more abundant than EPA. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others. It is converted to 17-hydroperoxy-DHA derivatives via COX-2 and 15-LOX and 5-LOX activity. These derivatives are further converted into D-series resolvins and protectins with potent anti-inflammatory potential and potent neuroprotective effect. DHA may also be metabolized to 19,20-epoxydocosapentaenoic acids (EDPs) and isomers via CYP2C9 activity. Epoxy metabolites are reported to mediate anti-tumor activity by inhibiting angiogenesis, tumor growth, and metastasis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Approximately 20 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral LD50 value in rats is 7,060 mg/kg and 3,450 mg/kg in mouse. Adverse effects include anemia, cough, CNS depression, drowsiness, headache, heart damage, lassitude (weakness, exhaustion), liver damage, narcosis, reproductive effects and teratogenic effects. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Animi-3 With Vitamin D, Citranatal Harmony •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 22:6(n-3) all-cis-DHA cervonic acid Doconexent Docosahexaenoic acid Docosahexanoic Acid •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doconexent is an omega 3 fatty acid used in a variety of nutritional supplements to support central nervous system and cardiovascular health. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Dofetilide interact?

•Drug A: Abatacept •Drug B: Dofetilide •Severity: MAJOR •Description: The metabolism of Dofetilide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): >90% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 3 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% -70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tikosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dofetilida Dofetilide Dofetilidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Dofetilide interact? Information: •Drug A: Abatacept •Drug B: Dofetilide •Severity: MAJOR •Description: The metabolism of Dofetilide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): >90% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 3 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% -70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tikosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dofetilida Dofetilide Dofetilidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Dolasetron interact?

•Drug A: Abatacept •Drug B: Dolasetron •Severity: MODERATE •Description: The metabolism of Dolasetron can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dolasetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT 3 receptor agonists. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dolasetron is a selective serotonin 5-HT 3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. The antiemetic activity of the drug is brought about through the inhibition of 5-HT 3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT 3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally-administered dolasetron is well absorbed •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 5.8 L/kg [adults] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 69-77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 8.1 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anzemet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dolasetron is an antinauseant and antiemetic used in chemotherapy and postoperatively.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Dolasetron interact? Information: •Drug A: Abatacept •Drug B: Dolasetron •Severity: MODERATE •Description: The metabolism of Dolasetron can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including initial and repeat courses of chemotherapy. Also used for the prevention of postoperative nausea and vomiting. This drug can be used intravenously for the treatment of postoperative nausea and vomiting. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dolasetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT 3 receptor agonists. The serontonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dolasetron is a selective serotonin 5-HT 3 receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. The antiemetic activity of the drug is brought about through the inhibition of 5-HT 3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT 3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally-administered dolasetron is well absorbed •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 5.8 L/kg [adults] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 69-77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Hydrodolasetron is eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation, and hydroxylation. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 8.1 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent cl=9.4 mL/min/kg [Healthy volunteers with IV treatment dose up to 5 mg/kg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anzemet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dolasetron is an antinauseant and antiemetic used in chemotherapy and postoperatively. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Domperidone interact?

•Drug A: Abatacept •Drug B: Domperidone •Severity: MODERATE •Description: The metabolism of Domperidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Domperidone is a specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic mechanisms. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Domperidone acts as a gastrointestinal emptying (delayed) adjunct and peristaltic stimulant. The gastroprokinetic properties of domperidone are related to its peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. Antiemetic: The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 91%-93% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include galactorrhea, gynecomastia, or menstrual irregularities. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Domperidona Domperidone Domperidonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Domperidone is a dopamine receptor antagonist used as a peristaltic stimulant and anti-emetic agent for dyspepsia, indigestion, epigastric pain, nausea, and vomiting.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Domperidone interact? Information: •Drug A: Abatacept •Drug B: Domperidone •Severity: MODERATE •Description: The metabolism of Domperidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For management of dyspepsia, heartburn, epigastric pain, nausea, and vomiting. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Domperidone is a specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic mechanisms. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Domperidone acts as a gastrointestinal emptying (delayed) adjunct and peristaltic stimulant. The gastroprokinetic properties of domperidone are related to its peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by lowering esophageal sphincter pressure. Antiemetic: The antiemetic properties of domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which - among others - regulates nausea and vomiting •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 91%-93% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include galactorrhea, gynecomastia, or menstrual irregularities. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Domperidona Domperidone Domperidonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Domperidone is a dopamine receptor antagonist used as a peristaltic stimulant and anti-emetic agent for dyspepsia, indigestion, epigastric pain, nausea, and vomiting. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Donepezil interact?

•Drug A: Abatacept •Drug B: Donepezil •Severity: MODERATE •Description: The metabolism of Donepezil can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Donepezil, administered orally or via transdermal delivery system, is indicated for the treatment of dementia of the Alzheimer's type. It is also available as an extended-release capsule in combination with memantine for the treatment of moderate-to-severe dementia of the Alzheimer's type in patients previously stabilized on 10mg of donepezil hydrochloride once daily. Off-label uses include the management of vascular dementia, Parkinson's Disease-associated dementia, and Lewy body dementia, amongst others. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): By inhibiting the acetylcholinesterase enzyme, donepezil improves the cognitive and behavioral signs and symptoms of Alzheimer's Disease, which may include apathy, aggression, confusion, and psychosis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's. Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Donepezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration. The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours. The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph. The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%. The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Donepezil is 96% protein-bound, with approximately 75% binding to albumin and approximately 21% binding to alpha-1-glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6. After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug. A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme. This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil.. One pharmacokinetic study determined the average terminal half-life to be 81.5±22.0 h •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): According to the FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg. A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg. In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 The rat oral LD50 of donepezil is 32.6 mg/kg. Overdose information Signs and symptoms of overdose with cholinesterase inhibitors such as donepezil can include severe nausea and vomiting, bradycardia, hypotension, perspiration, seizures, muscle weakness respiratory depression, and collapse. Significant muscle weakness may result in death if the respiratory muscles are affected by donepezil overdose. To manage an overdose, anticholinergics can be employed as antidotes. Atropine at intravenous doses of 1.0 - 2.0 mg can be administered and titrated according to the clinical response. Consult the local poison control center for the most updated guidelines on the management of a donepezil overdose. Whether donepezil can be removed from the body with dialysis is unknown at this time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adlarity, Aricept, Namzaric •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Donepezil is an acetylcholinesterase inhibitor used to treat the behavioral and cognitive effects of Alzheimer's Disease and other types of dementia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Donepezil interact? Information: •Drug A: Abatacept •Drug B: Donepezil •Severity: MODERATE •Description: The metabolism of Donepezil can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Donepezil, administered orally or via transdermal delivery system, is indicated for the treatment of dementia of the Alzheimer's type. It is also available as an extended-release capsule in combination with memantine for the treatment of moderate-to-severe dementia of the Alzheimer's type in patients previously stabilized on 10mg of donepezil hydrochloride once daily. Off-label uses include the management of vascular dementia, Parkinson's Disease-associated dementia, and Lewy body dementia, amongst others. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): By inhibiting the acetylcholinesterase enzyme, donepezil improves the cognitive and behavioral signs and symptoms of Alzheimer's Disease, which may include apathy, aggression, confusion, and psychosis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's. Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Donepezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration. The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours. The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph. The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%. The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Donepezil is 96% protein-bound, with approximately 75% binding to albumin and approximately 21% binding to alpha-1-glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6. After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug. A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme. This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil.. One pharmacokinetic study determined the average terminal half-life to be 81.5±22.0 h •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): According to the FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg. A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg. In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 The rat oral LD50 of donepezil is 32.6 mg/kg. Overdose information Signs and symptoms of overdose with cholinesterase inhibitors such as donepezil can include severe nausea and vomiting, bradycardia, hypotension, perspiration, seizures, muscle weakness respiratory depression, and collapse. Significant muscle weakness may result in death if the respiratory muscles are affected by donepezil overdose. To manage an overdose, anticholinergics can be employed as antidotes. Atropine at intravenous doses of 1.0 - 2.0 mg can be administered and titrated according to the clinical response. Consult the local poison control center for the most updated guidelines on the management of a donepezil overdose. Whether donepezil can be removed from the body with dialysis is unknown at this time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adlarity, Aricept, Namzaric •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Donepezil is an acetylcholinesterase inhibitor used to treat the behavioral and cognitive effects of Alzheimer's Disease and other types of dementia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Doravirine interact?

•Drug A: Abatacept •Drug B: Doravirine •Severity: MODERATE •Description: The metabolism of Doravirine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In a clinical phase 2 trial evaluating a dose range of 0.25-2x the recommended dose of doravirine (in combination with emtricitabine/tenofovir) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Furthermore, at a dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose, doravirine does not prolong the QT interval to any clinically relevant extent. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1. Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome - this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication. Doravirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase. Doravirine does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of doravirine is 64% with a T max of 2 hours. Following oral [14C]doravirine administration, all of the administered dose was recovered and the agent is considered to be well absorbed. Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Doravirine is approximately 76% protein-bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following absorption, unchanged parent drug is the major circulating component in plasma. Its M9 metabolite - a product of cytochrome P450 3A4/5 mediated oxidative metabolism - is the most abundant doravirine metabolite in the circulation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism. Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life determined of doravirine is 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown. No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes. It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine. The safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy. No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients. No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Delstrigo, Pifeltro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doravirine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals to treat HIV-1 infections.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Doravirine interact? Information: •Drug A: Abatacept •Drug B: Doravirine •Severity: MODERATE •Description: The metabolism of Doravirine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In a clinical phase 2 trial evaluating a dose range of 0.25-2x the recommended dose of doravirine (in combination with emtricitabine/tenofovir) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Furthermore, at a dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose, doravirine does not prolong the QT interval to any clinically relevant extent. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1. Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome - this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication. Doravirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase. Doravirine does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of doravirine is 64% with a T max of 2 hours. Following oral [14C]doravirine administration, all of the administered dose was recovered and the agent is considered to be well absorbed. Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Doravirine is approximately 76% protein-bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following absorption, unchanged parent drug is the major circulating component in plasma. Its M9 metabolite - a product of cytochrome P450 3A4/5 mediated oxidative metabolism - is the most abundant doravirine metabolite in the circulation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism. Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life determined of doravirine is 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown. No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes. It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine. The safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy. No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients. No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Delstrigo, Pifeltro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doravirine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals to treat HIV-1 infections. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Dosulepin interact?

•Drug A: Abatacept •Drug B: Dosulepin •Severity: MAJOR •Description: The metabolism of Dosulepin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug. Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect. Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 84% of unchanged drug is bound to serum protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg. Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dosulepin Dosulepina Dosulépine Dosulepinum Dothiepin trans-dothiepin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dosulepin is a tricyclic antidepressant commonly used only in patients for whom alternative therapies are ineffective due to its toxicity potential.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Dosulepin interact? Information: •Drug A: Abatacept •Drug B: Dosulepin •Severity: MAJOR •Description: The metabolism of Dosulepin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug. Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect. Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 84% of unchanged drug is bound to serum protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg. Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dosulepin Dosulepina Dosulépine Dosulepinum Dothiepin trans-dothiepin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dosulepin is a tricyclic antidepressant commonly used only in patients for whom alternative therapies are ineffective due to its toxicity potential. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Doxazosin interact?

•Drug A: Abatacept •Drug B: Doxazosin •Severity: MODERATE •Description: The metabolism of Doxazosin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doxazosin is indicated to treat the symptoms of benign prostatic hypertrophy, which may include urinary frequency, urgency, and nocturia, among other symptoms. In addition, doxazosin is indicated alone or in combination with various antihypertensive agents for the management of hypertension. Off-label uses of doxazosin include the treatment of pediatric hypertension and the treatment of ureteric calculi. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of doxazosin is 1.0-1.9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of doxazosin is estimated at 98%.. It has also been shown to be bound to the alpha-1 acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of doxazosin has been estimated at 9-12 hours according to some resources. The FDA label indicates the elimination half-life of doxazosin is 22 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 information The oral LD50 of doxazosin in mice is >1000 mg/kg. Overdose information Symptoms of overdose include hypotension, changes in heart rate, and drowsiness. Administer supportive treatment in case of an overdose with doxazosin. Remove unabsorbed doxazosin from the gastrointestinal tract, correct hypotension, and closely monitor vital signs. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cardura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Doxazosin Doxazosina Doxazosine Doxazosinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxazosin is an alpha-1 adrenergic receptor used to treat mild to moderate hypertension and urinary obstruction due to benign prostatic hyperplasia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Doxazosin interact? Information: •Drug A: Abatacept •Drug B: Doxazosin •Severity: MODERATE •Description: The metabolism of Doxazosin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doxazosin is indicated to treat the symptoms of benign prostatic hypertrophy, which may include urinary frequency, urgency, and nocturia, among other symptoms. In addition, doxazosin is indicated alone or in combination with various antihypertensive agents for the management of hypertension. Off-label uses of doxazosin include the treatment of pediatric hypertension and the treatment of ureteric calculi. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of doxazosin is 1.0-1.9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of doxazosin is estimated at 98%.. It has also been shown to be bound to the alpha-1 acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of doxazosin has been estimated at 9-12 hours according to some resources. The FDA label indicates the elimination half-life of doxazosin is 22 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 information The oral LD50 of doxazosin in mice is >1000 mg/kg. Overdose information Symptoms of overdose include hypotension, changes in heart rate, and drowsiness. Administer supportive treatment in case of an overdose with doxazosin. Remove unabsorbed doxazosin from the gastrointestinal tract, correct hypotension, and closely monitor vital signs. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cardura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Doxazosin Doxazosina Doxazosine Doxazosinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxazosin is an alpha-1 adrenergic receptor used to treat mild to moderate hypertension and urinary obstruction due to benign prostatic hyperplasia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Doxepin interact?

•Drug A: Abatacept •Drug B: Doxepin •Severity: MODERATE •Description: The metabolism of Doxepin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Oral doxepin is approved for the following indications: Treatment of depression and/or anxiety. Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. Treatment of psychotic depressive disorders with associated anxiety. Treatment of involutional depression. Treatment of manic-depressive disorder. Treatment of insomnia characterized by difficulties with sleep maintenance. Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus. Off-label, doxepin is used topically for the management of neuropathic pain. Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment. Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder. Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic. Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner. Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean elimination half-life is reported to be of 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prudoxin, Silenor, Sinequan, Zonalon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxepin is a psychotropic agent used for the treatment of depression, anxiety, manic-depressive disorder, and insomnia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Doxepin interact? Information: •Drug A: Abatacept •Drug B: Doxepin •Severity: MODERATE •Description: The metabolism of Doxepin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Oral doxepin is approved for the following indications: Treatment of depression and/or anxiety. Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. Treatment of psychotic depressive disorders with associated anxiety. Treatment of involutional depression. Treatment of manic-depressive disorder. Treatment of insomnia characterized by difficulties with sleep maintenance. Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus. Off-label, doxepin is used topically for the management of neuropathic pain. Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment. Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder. Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic. Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner. Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean elimination half-life is reported to be of 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prudoxin, Silenor, Sinequan, Zonalon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxepin is a psychotropic agent used for the treatment of depression, anxiety, manic-depressive disorder, and insomnia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Doxorubicin interact?

•Drug A: Abatacept •Drug B: Doxorubicin •Severity: MAJOR •Description: The metabolism of Doxorubicin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doxorubicin is indicated for the treatment of neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin and non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue and bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, and metastatic bronchogenic carcinoma. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer. For the liposomal formulation, doxorubicin is indicated for the treatment of ovarian cancer that has progressed or recurred after platinum-based chemotherapy, AIDS-Related Kaposi's Sarcoma after the failure of prior systemic chemotherapy or intolerance to such therapy, and multiple myeloma in combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Doxorubicin is a cytotoxic, cell-cycle non-specific anthracycline antibiotic. It is generally thought to exert its antitumor effect by destabilizing DNA structures through intercalation, thus introducing DNA strand breakages and damages. Not only does it alter the transcriptomes of the cells, failure in repairing DNA structures can also initiate the apoptotic pathways. Additionally, doxorubicin intercalation can also interfere with vital enzyme activity, such as topoisomerase II, DNA polymerase, and RNA polymerase, leading to cell cycle arrests. Finally, doxorubicin can also generate cytotoxic reactive oxygen species to exert cellular damages. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Generally, doxorubicin is thought to exert its antineoplastic activity through 2 primary mechanisms: intercalation into DNA and disrupt topoisomerase-mediated repairs and free radicals-mediated cellular damages. Doxorubicin can intercalate into DNA through the anthraquinone ring, which stabilizes the complex by forming hydrogen bonds with DNA bases. Intercalation of doxorubicin can introduce torsional stress into the polynucleotide structure, thus destabilizing nucleosome structures and leading to nucleosome eviction and replacement. Additionally, the doxorubicin-DNA complex can interfere with topoisomerase II enzyme activity by preventing relegation of topoisomerase-mediated DNA breaks, thus inhibiting replication and transcription and inducing apoptosis. Moreover, doxorubicin can be metabolized by microsomal NADPH-cytochrome P-450 reductase into a semiquinone radical, which can be reoxidized in the presence of oxygen to form oxygen radicals. Reactive oxygen species have been known to cause cellular damage through various mechanisms, including lipid peroxidation and membrane damage, DNA damage, oxidative stress, and apoptosis. Although free radicals generated from this pathway can be deactivated by catalase and superoxide dismutase, tumor and myocardial cells tend to lack these enzymes, thus explaining doxorubicin's effectiveness against cancer cells and tendency to cause cardiotoxicity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a 10 mg/m administration of liposomal doxorubicin in patients with AIDS-related Kaposi's Sarcoma, the C max and AUC values were calculated to be 4.12 ± 0.215 μg/mL and 277 ± 32.9 μg/mL•h respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state distribution volume of doxorubicin ranges from 809 L/m to 1214 L/m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL. Doxorubicin does not cross the blood-brain barrier. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Doxorubicin is capable of undergoing 3 metabolic routes: one-electron reduction, two-electron reduction, and deglycosidation. However, approximately half of the dose is eliminated from the body unchanged. The two-electron reduction is the major metabolic pathway of doxorubicin. In this pathway, doxorubicin is reduced to doxorubicinol, a secondary alcohol, by various enzymes, including Alcohol dehydrogenase [NADP(+)], Carbonyl reductase NADPH 1, Carbonyl reductase NADPH 3, and Aldo-keto reductase family 1 member C3. The one-electron reduction is facilitated by several oxidoreductase, both cytosolic and mitochondrial, to form a doxirubicin-semiquinone radical. These enzymes include mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. This semiquinone metabolite can be re-oxidized to doxorubicin, although with the concurrent formation of reactive oxygen species (ROS) and hydrogen peroxide. It is the ROS generating through this pathway that contributes most to the doxorubicin-related adverse effects, particularly cardiotoxicity, rather than through doxorubicin semiquinone formation. Deglycosidation is a minor metabolic pathway, since it only accounts for 1 to 2% of doxorubicin metabolism. Under the catalysis of cytoplasmic NADPH quinone dehydrogenase, xanthine oxidase, NADPH-cytochrome P450 reductase, doxorubicin can either be reduced to doxorubicin deoxyaglycone or hydrolyzed to doxorubicin hydroxyaglycone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 40% of the dose appears in the bile in 5 days, while only 5% to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-life of doxorubicin ranges from 20 hours to 48 hours. The distribution half-life of doxorubicin is approximately 5 minutes. For the liposomal formulation, the first-phase and second-phase half-lives were calculated to be 4.7 ± 1.1 and 52.3 ± 5.6 hours respectively for a 10 mg/m of doxorubicin in patients with AIDS-Related Kaposi’s Sarcoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The plasma clearance of doxorubicin ranges from 324 mL/min/m2 to 809 mL/min/m by metabolism and biliary excretion. Sexual differences in doxorubicin were also observed, with men having a higher clearance compared to women (1088 mL/min/m versus 433 mL/min/m ). Following the administration of doses ranging from 10 mg/m2 to 75 mg/m of doxorubicin hydrochloride, the plasma clearance was estimated to be 1540 mL/min/m in children greater than 2 years of age and 813 mL/min/m in infants younger than 2 years of age. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports. Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. Doxorubicin hydrochloride decreased fertility in female rats at doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment. A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection/for Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2. Advise pregnant women of the potential risk to a fetus. Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adriamycin, Doxil, Myocet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 14-hydroxydaunomycin 14-hydroxydaunorubicine Doxorubicin Doxorubicin nanoparticles Doxorubicina Doxorubicine Doxorubicinum Hydroxydaunorubicin MTC-DOX MTC-DOX for Injection •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxorubicin is a medication used to treat various cancers, including AIDS-associated Kaposi's Sarcoma and metastatic cancers.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Doxorubicin interact? Information: •Drug A: Abatacept •Drug B: Doxorubicin •Severity: MAJOR •Description: The metabolism of Doxorubicin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Doxorubicin is indicated for the treatment of neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin and non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue and bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, and metastatic bronchogenic carcinoma. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer. For the liposomal formulation, doxorubicin is indicated for the treatment of ovarian cancer that has progressed or recurred after platinum-based chemotherapy, AIDS-Related Kaposi's Sarcoma after the failure of prior systemic chemotherapy or intolerance to such therapy, and multiple myeloma in combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Doxorubicin is a cytotoxic, cell-cycle non-specific anthracycline antibiotic. It is generally thought to exert its antitumor effect by destabilizing DNA structures through intercalation, thus introducing DNA strand breakages and damages. Not only does it alter the transcriptomes of the cells, failure in repairing DNA structures can also initiate the apoptotic pathways. Additionally, doxorubicin intercalation can also interfere with vital enzyme activity, such as topoisomerase II, DNA polymerase, and RNA polymerase, leading to cell cycle arrests. Finally, doxorubicin can also generate cytotoxic reactive oxygen species to exert cellular damages. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Generally, doxorubicin is thought to exert its antineoplastic activity through 2 primary mechanisms: intercalation into DNA and disrupt topoisomerase-mediated repairs and free radicals-mediated cellular damages. Doxorubicin can intercalate into DNA through the anthraquinone ring, which stabilizes the complex by forming hydrogen bonds with DNA bases. Intercalation of doxorubicin can introduce torsional stress into the polynucleotide structure, thus destabilizing nucleosome structures and leading to nucleosome eviction and replacement. Additionally, the doxorubicin-DNA complex can interfere with topoisomerase II enzyme activity by preventing relegation of topoisomerase-mediated DNA breaks, thus inhibiting replication and transcription and inducing apoptosis. Moreover, doxorubicin can be metabolized by microsomal NADPH-cytochrome P-450 reductase into a semiquinone radical, which can be reoxidized in the presence of oxygen to form oxygen radicals. Reactive oxygen species have been known to cause cellular damage through various mechanisms, including lipid peroxidation and membrane damage, DNA damage, oxidative stress, and apoptosis. Although free radicals generated from this pathway can be deactivated by catalase and superoxide dismutase, tumor and myocardial cells tend to lack these enzymes, thus explaining doxorubicin's effectiveness against cancer cells and tendency to cause cardiotoxicity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a 10 mg/m administration of liposomal doxorubicin in patients with AIDS-related Kaposi's Sarcoma, the C max and AUC values were calculated to be 4.12 ± 0.215 μg/mL and 277 ± 32.9 μg/mL•h respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state distribution volume of doxorubicin ranges from 809 L/m to 1214 L/m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL. Doxorubicin does not cross the blood-brain barrier. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Doxorubicin is capable of undergoing 3 metabolic routes: one-electron reduction, two-electron reduction, and deglycosidation. However, approximately half of the dose is eliminated from the body unchanged. The two-electron reduction is the major metabolic pathway of doxorubicin. In this pathway, doxorubicin is reduced to doxorubicinol, a secondary alcohol, by various enzymes, including Alcohol dehydrogenase [NADP(+)], Carbonyl reductase NADPH 1, Carbonyl reductase NADPH 3, and Aldo-keto reductase family 1 member C3. The one-electron reduction is facilitated by several oxidoreductase, both cytosolic and mitochondrial, to form a doxirubicin-semiquinone radical. These enzymes include mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. This semiquinone metabolite can be re-oxidized to doxorubicin, although with the concurrent formation of reactive oxygen species (ROS) and hydrogen peroxide. It is the ROS generating through this pathway that contributes most to the doxorubicin-related adverse effects, particularly cardiotoxicity, rather than through doxorubicin semiquinone formation. Deglycosidation is a minor metabolic pathway, since it only accounts for 1 to 2% of doxorubicin metabolism. Under the catalysis of cytoplasmic NADPH quinone dehydrogenase, xanthine oxidase, NADPH-cytochrome P450 reductase, doxorubicin can either be reduced to doxorubicin deoxyaglycone or hydrolyzed to doxorubicin hydroxyaglycone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 40% of the dose appears in the bile in 5 days, while only 5% to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-life of doxorubicin ranges from 20 hours to 48 hours. The distribution half-life of doxorubicin is approximately 5 minutes. For the liposomal formulation, the first-phase and second-phase half-lives were calculated to be 4.7 ± 1.1 and 52.3 ± 5.6 hours respectively for a 10 mg/m of doxorubicin in patients with AIDS-Related Kaposi’s Sarcoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The plasma clearance of doxorubicin ranges from 324 mL/min/m2 to 809 mL/min/m by metabolism and biliary excretion. Sexual differences in doxorubicin were also observed, with men having a higher clearance compared to women (1088 mL/min/m versus 433 mL/min/m ). Following the administration of doses ranging from 10 mg/m2 to 75 mg/m of doxorubicin hydrochloride, the plasma clearance was estimated to be 1540 mL/min/m in children greater than 2 years of age and 813 mL/min/m in infants younger than 2 years of age. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports. Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. Doxorubicin hydrochloride decreased fertility in female rats at doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment. A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection/for Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2. Advise pregnant women of the potential risk to a fetus. Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adriamycin, Doxil, Myocet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 14-hydroxydaunomycin 14-hydroxydaunorubicine Doxorubicin Doxorubicin nanoparticles Doxorubicina Doxorubicine Doxorubicinum Hydroxydaunorubicin MTC-DOX MTC-DOX for Injection •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Doxorubicin is a medication used to treat various cancers, including AIDS-associated Kaposi's Sarcoma and metastatic cancers. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Dronabinol interact?

•Drug A: Abatacept •Drug B: Dronabinol •Severity: MODERATE •Description: The metabolism of Dronabinol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Dronabinol is indicated for the treatment of anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing. Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol capsules have an onset of action of approximately 0.5 to 1 hour and a peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Tachyphylaxis and tolerance develop to some of the cardiovascular and CNS pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules in divided doses for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis (marijuana). THC demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, which results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dronabinol is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first-pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions, with the C max and AUC inf of 1.9 ± 1.3 ng/mL and 3.8 ± 1.8 ng.h/mL respectively. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (C max and AUC inf ) was approximately 66% and 47% and 67% and 14%, respectively, following the administration of SYNDROS to healthy subjects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of dronabinol and its metabolites is approximately 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): THC is primarily metabolized in the liver by microsomal hydroxylation and oxidation reactions catalyzed by Cytochrome P450 enzymes. 11-hydroxy-▵9-tetrahydrocannabinol (11-OH-THC) is the primary active metabolite, capable of producing psychological and behavioural effects, which is then metabolized into 11-nor-9-carboxy-▵ 9-tetrahydrocannabinol (THC-COOH), THC's primary inactive metabolite. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radiolabeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Due to its redistribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single-dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six-week period. The urinary cannabinoid/creatinine ratio was closely correlated with the dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination phase of dronabinol can be described using a two-compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The value for clearance average is about 0.2 L/kg-hr but is highly variable due to the complexity of cannabinoid distribution. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): SYNDROS, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid the use of SYNDROS in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, the use of cannabis (e.g., marijuana) and the use of alcohol during pregnancy have been associated with adverse fetal/neonatal outcomes (see Clinical Considerations). Cannabinoids have been found in the umbilical cord blood of pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol (delta-9-THC) at up to 30 times the MRHD (maximum recommended human doses) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and the number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses that induced maternal toxicity. In rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity, including mortality of pups, and adverse developmental and 10 neurodevelopmental effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less than and up to 3.3 times the MRHD for patients with cancer. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in 12 HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving SYNDROS. For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNDROS and any potential adverse effects on the breastfed infant from SYNDROS or from the underlying maternal condition. The safety and effectiveness of SYNDROS have not been established in pediatric patients. Pediatric patients may be more sensitive to the neurological and psychoactive effects of SYNDROS. SYNDROS contains the excipients 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby, leading to accumulation. Clinical studies of dronabinol capsules in AIDS and cancer patients did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of SYNDROS. Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with SYNDROS. These patients should be monitored closely and placed on fall precautions prior to initiating SYNDROS therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and concomitant disease or other drugs therapy. SYNDROS contains dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia. In vitro studies demonstrate that SYNDROS can be easily and effectively abused without manipulation. SYNDROS contains 50% (w/w) dehydrated alcohol. In a randomized, single-dose, double-blind, placebo- and active-controlled crossover pharmacodynamic study of 43 experienced marijuana smokers, “drug liking” responses and safety of SYNDROS were compared with placebo and dronabinol in sesame oil oral capsules. Treatment arms were 10 mg and 30 mg dronabinol capsules, 10 mg and 30 mg dronabinol from= SYNDROS, and placebo oral solution and capsules. Greater “drug liking” scores were reported with the 30 mg dose, compared with the 10 mg dose, for both SYNDROS and dronabinol-containing capsules. Overall, the pharmacodynamic results from this study demonstrated no statistically significant differences in various measures of drug liking for the doses taken, though the SYNDROS results were consistently greater than those of dronabinol capsules. Similarly, observed adverse reactions were greater for SYNDROS. The pharmacodynamic and safety effects of SYNDROS following multiple doses have not been evaluated. Patients should be instructed to keep SYNDROS in a secure place out of reach of others for whom the medication has not been prescribed. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when the administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with SYNDROS and develops after chronic abuse of marijuana. A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol capsules in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol. Signs and symptoms of dronabinol overdose include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety and seizures may occur in patients with existing seizure disorders. It is not known if dronabinol can be removed by dialysis in cases of overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Marinol, Sativex, Syndros •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): .DELTA.1-THC delta-9-THC delta(9)-THC Dronabinol Dronabinolum Tetrahydrocannabinol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dronabinol is a synthetic delta-9-THC used in the treatment of anorexia and weight loss in HIV patients as well as nausea and vomiting in cancer chemotherapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Dronabinol interact? Information: •Drug A: Abatacept •Drug B: Dronabinol •Severity: MODERATE •Description: The metabolism of Dronabinol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Dronabinol is indicated for the treatment of anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing. Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol capsules have an onset of action of approximately 0.5 to 1 hour and a peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Tachyphylaxis and tolerance develop to some of the cardiovascular and CNS pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules in divided doses for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis (marijuana). THC demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, which results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dronabinol is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first-pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions, with the C max and AUC inf of 1.9 ± 1.3 ng/mL and 3.8 ± 1.8 ng.h/mL respectively. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (C max and AUC inf ) was approximately 66% and 47% and 67% and 14%, respectively, following the administration of SYNDROS to healthy subjects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of dronabinol and its metabolites is approximately 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): THC is primarily metabolized in the liver by microsomal hydroxylation and oxidation reactions catalyzed by Cytochrome P450 enzymes. 11-hydroxy-▵9-tetrahydrocannabinol (11-OH-THC) is the primary active metabolite, capable of producing psychological and behavioural effects, which is then metabolized into 11-nor-9-carboxy-▵ 9-tetrahydrocannabinol (THC-COOH), THC's primary inactive metabolite. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radiolabeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Due to its redistribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single-dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six-week period. The urinary cannabinoid/creatinine ratio was closely correlated with the dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination phase of dronabinol can be described using a two-compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The value for clearance average is about 0.2 L/kg-hr but is highly variable due to the complexity of cannabinoid distribution. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): SYNDROS, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid the use of SYNDROS in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, the use of cannabis (e.g., marijuana) and the use of alcohol during pregnancy have been associated with adverse fetal/neonatal outcomes (see Clinical Considerations). Cannabinoids have been found in the umbilical cord blood of pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol (delta-9-THC) at up to 30 times the MRHD (maximum recommended human doses) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and the number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses that induced maternal toxicity. In rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity, including mortality of pups, and adverse developmental and 10 neurodevelopmental effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less than and up to 3.3 times the MRHD for patients with cancer. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in 12 HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving SYNDROS. For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNDROS and any potential adverse effects on the breastfed infant from SYNDROS or from the underlying maternal condition. The safety and effectiveness of SYNDROS have not been established in pediatric patients. Pediatric patients may be more sensitive to the neurological and psychoactive effects of SYNDROS. SYNDROS contains the excipients 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby, leading to accumulation. Clinical studies of dronabinol capsules in AIDS and cancer patients did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of SYNDROS. Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with SYNDROS. These patients should be monitored closely and placed on fall precautions prior to initiating SYNDROS therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and concomitant disease or other drugs therapy. SYNDROS contains dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia. In vitro studies demonstrate that SYNDROS can be easily and effectively abused without manipulation. SYNDROS contains 50% (w/w) dehydrated alcohol. In a randomized, single-dose, double-blind, placebo- and active-controlled crossover pharmacodynamic study of 43 experienced marijuana smokers, “drug liking” responses and safety of SYNDROS were compared with placebo and dronabinol in sesame oil oral capsules. Treatment arms were 10 mg and 30 mg dronabinol capsules, 10 mg and 30 mg dronabinol from= SYNDROS, and placebo oral solution and capsules. Greater “drug liking” scores were reported with the 30 mg dose, compared with the 10 mg dose, for both SYNDROS and dronabinol-containing capsules. Overall, the pharmacodynamic results from this study demonstrated no statistically significant differences in various measures of drug liking for the doses taken, though the SYNDROS results were consistently greater than those of dronabinol capsules. Similarly, observed adverse reactions were greater for SYNDROS. The pharmacodynamic and safety effects of SYNDROS following multiple doses have not been evaluated. Patients should be instructed to keep SYNDROS in a secure place out of reach of others for whom the medication has not been prescribed. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when the administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with SYNDROS and develops after chronic abuse of marijuana. A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol capsules in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol. Signs and symptoms of dronabinol overdose include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety and seizures may occur in patients with existing seizure disorders. It is not known if dronabinol can be removed by dialysis in cases of overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Marinol, Sativex, Syndros •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): .DELTA.1-THC delta-9-THC delta(9)-THC Dronabinol Dronabinolum Tetrahydrocannabinol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dronabinol is a synthetic delta-9-THC used in the treatment of anorexia and weight loss in HIV patients as well as nausea and vomiting in cancer chemotherapy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Dronedarone interact?

•Drug A: Abatacept •Drug B: Dronedarone •Severity: MAJOR •Description: The metabolism of Dronedarone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Dronedarone is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound amiodarone, dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke. Dronedarone achieves heart rate and rhythm control in atrial fibrillation. In vitro, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively. Both mainly bind to albumin and are not capable of saturation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dronedarone predominantly undergoes CYP3A-mediated hepatic metabolism. Initial metabolism of dronedarone involves N-debutylation to form the N-debutyl-dronedarone, which retains 1/10 to 1/3 of pharmacological activity of the parent compound. N-debutyl-dronedarone can be further metabolized to phenol-dronedarone via O-dealkylation and propanoic acid-dronedarone via oxidative deamination. Dronedarone can also be metabolized by CYP2D6 to form benzofuran-hydroxyl-dronedarone. Other detectable metabolites include C-dealkyl-dronedarone and dibutylamine-hydroxyl-dronedarone, along with other minor downstream metabolites with undetermined chemical structures. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half life ranges from 13 to 19 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration, the clearance ranged from 130 to 150 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an acute toxicity study, the oral LD 50 in rat was >2,000 mg/kg. In oral studies, dronedarone showed a limited potential for toxicity in humans in acute overdose situations. However, it is recommended that the patient's cardiac rhythm and blood pressure is monitored in the event of overdose. Symptomatic and supportive treatments should be initiated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Multaq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dronedarona Dronedarone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dronedarone is an antiarrhythmic agent used in the reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Dronedarone interact? Information: •Drug A: Abatacept •Drug B: Dronedarone •Severity: MAJOR •Description: The metabolism of Dronedarone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Dronedarone is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound amiodarone, dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke. Dronedarone achieves heart rate and rhythm control in atrial fibrillation. In vitro, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively. Both mainly bind to albumin and are not capable of saturation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dronedarone predominantly undergoes CYP3A-mediated hepatic metabolism. Initial metabolism of dronedarone involves N-debutylation to form the N-debutyl-dronedarone, which retains 1/10 to 1/3 of pharmacological activity of the parent compound. N-debutyl-dronedarone can be further metabolized to phenol-dronedarone via O-dealkylation and propanoic acid-dronedarone via oxidative deamination. Dronedarone can also be metabolized by CYP2D6 to form benzofuran-hydroxyl-dronedarone. Other detectable metabolites include C-dealkyl-dronedarone and dibutylamine-hydroxyl-dronedarone, along with other minor downstream metabolites with undetermined chemical structures. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half life ranges from 13 to 19 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration, the clearance ranged from 130 to 150 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an acute toxicity study, the oral LD 50 in rat was >2,000 mg/kg. In oral studies, dronedarone showed a limited potential for toxicity in humans in acute overdose situations. However, it is recommended that the patient's cardiac rhythm and blood pressure is monitored in the event of overdose. Symptomatic and supportive treatments should be initiated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Multaq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dronedarona Dronedarone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dronedarone is an antiarrhythmic agent used in the reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Drospirenone interact?

•Drug A: Abatacept •Drug B: Drospirenone •Severity: MODERATE •Description: The metabolism of Drospirenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Drospirenone, in combination with ethinyl estradiol or estetrol, is indicated as an oral contraceptive for the prevention of pregnancy. In addition to its use for contraceptive effects, this combination is used to treat moderate acne vulgaris and the symptoms of premenstrual dysphoric disorder. The drug has approved indications for combination with estrogens for the treatment of menopause-associated symptoms, such as vasomotor symptoms and vulvovaginal atrophy. Drospirenone combined with estrogen may also may aid in the prevention of osteoporosis in women who have been post-menopausal for at least a year and are not candidates for other therapies. It can sometimes be found in preparations containing estrogen and folic acid for folic acid replenishment during oral contraception. When used for the treatment of acne vulgaris, drospirenone-containing contraceptives should only be used in women ≥14 years of age who have experienced menarche, desire oral contraception, and do not have any contraindications to oral contraceptives. Off-label uses for this drug include the treatment of menstrual irregularities, dysmenorrhea, hirsutism, and endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Drospirenone inhibits the maturation of follicles and inhibits ovulation, preventing pregnancy. It has antiandrogen effects, improving acne and hirsutism. When combined with ethinyl estradiol, it has been shown to have favorable effects on the plasma lipid profile. Due to its similarity to naturally occurring progesterone, drospirenone is thought to be associated with a lower incidence of progesterone contraceptive related adverse effects, such as breast tenderness and mood swings. A note on venous thromboembolism risk and antimineralcorticoid effects As with other oral contraceptives, the risk of venous thromboembolism and cardiovascular events may be increased when drospirenone is taken. The risk is especially higher in smokers and women aged 35 and older. Women taking this drug should be advised not to smoke. In addition, drospirenone, due to its antimineralcorticoid effects, may increase the risk of hyperkalemia. Patients at high risk for hyperkalemia should not be administered this drug. Consult the official prescribing information for detailed and updated information on the cardiovascular and other risks associated with drospirenone use. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Other changes induced by this drug which may aid in the prevention of pregnancy include alterations in cervical mucus consistency, hindering sperm movement, and lowering the chance of embryo implantation. Drospirenone is an analog of the diuretic spironolactone, which exerts anti-mineralocorticoid activity, blocking aldosterone receptors, which increases sodium and water excretion. Studies in animals have demonstrated that drospirenone administration leads to antiandrogenic activity. This activity helps to oppose the effects of naturally occurring androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptor, and preventing androgen synthesis in the ovaries, helping to treat acne and hirsutism. Drospirenone may also decrease the level of edema in sebaceous follicle during the second half of the menstrual cycle, when acne often appears. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of drospirenone is approximately 76% due to first-pass effects. The maximum plasma concentration of drospirenone occurs within 1 to 2 hours after oral administration and is estimated to range between 60 and 87 ng/mL. A European prescribing monograph for the combination product of estradiol and drospirenone indicates that drospirenone is both completely and rapidly absorbed. It reports a Cmax of 21.9 ng/ml, achieved approximately 1-hour post-administration. The absolute bioavailability is reported to range between 76 to 85%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of drospirenone is estimated to be 4 L/kg, according to the FDA label for Yaz. Prescribing information from a combination of estradiol and drospirenone estimates the volume of distribution to range from 3.7- 4.2 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Drospirenone is about 95% to 97% bound to serum plasma protein, likely to albumin. During in vitro studies, drospirenone was found to bind with low affinity to sex hormone-binding globulin (SHBG). Another reference indicates that drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG), nor corticoid binding globulin (CBG). Only 3-5% of the total drospirenone concentration is measured as a free steroid. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Drospirenone is heavily metabolized. The two major inactive metabolites identified are the acid form of drospirenone produced by the opening of its lactone ring, known as M11, and the 4,5-dihydro-drospirenone-3-sulfate (M14). Drospirenone also undergoes oxidative metabolism via the hepatic cytochrome enzyme CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Various metabolites of drospirenone are measured in the urine and feces. Drospirenone elimination from the body is almost after 10 days post-administration when negligible amounts of drospirenone are found unchanged in both the urine and feces. Between 38% to 47% of the metabolites are identified as glucuronide and sulfate conjugates in the urine. In the feces, approximately 17% to 20% of identifiable metabolites are found to be excreted as glucuronides and sulfates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The serum half-life of drospirenone is estimated to be 30 hours. The half-life of drospirenone metabolite excretion in the urine and feces is approximately 40 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Drospirenone is rapidly cleared, typically within 2-3 days of administration of the last active tablet. The rate of clearance of drospirenone calculated in the serum ranges from 1.2-1.5 ml/min/kg, however, this value can vary by up to 25% according to the patient. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 of drospirenone in rats is >2000 mg/kg. Overdose information An overdose of drospirenone, like other oral contraceptives, may lead to cause nausea or withdrawal bleeding. For drospirenone in particular, as an analog of spironolactone, may affect the levels of serum sodium and potassium. Their concentrations should be monitored in cases of overdose in addition to monitoring from metabolic acidosis and hyperkalemia, which may also result. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Angeliq 0.25/0.5 28 Day, Beyaz 28 Day, Gianvi 28-day, Jasmiel 28 Day, Lo-zumandimine 28 Day, Loryna, Nextstellis 28 Day, Nikki 28 Day, Ocella 28 Day, Safyral 28 Day, Slynd, Syeda 28 Day, Tydemy 28 Day, Vestura, Yasmin, Yasmin 28 Day, Yaz 28 Day, Yaz Plus, Zarah, Zumandimine 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,2-Dihydrospirorenone Dehydrospirorenone Drospirenona Drospirenone Drospirénone Drospirenonum DRSP •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Drospirenone is a progestin used in oral contraceptive pills for the prevention of pregnancy and other conditions.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Drospirenone interact? Information: •Drug A: Abatacept •Drug B: Drospirenone •Severity: MODERATE •Description: The metabolism of Drospirenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Drospirenone, in combination with ethinyl estradiol or estetrol, is indicated as an oral contraceptive for the prevention of pregnancy. In addition to its use for contraceptive effects, this combination is used to treat moderate acne vulgaris and the symptoms of premenstrual dysphoric disorder. The drug has approved indications for combination with estrogens for the treatment of menopause-associated symptoms, such as vasomotor symptoms and vulvovaginal atrophy. Drospirenone combined with estrogen may also may aid in the prevention of osteoporosis in women who have been post-menopausal for at least a year and are not candidates for other therapies. It can sometimes be found in preparations containing estrogen and folic acid for folic acid replenishment during oral contraception. When used for the treatment of acne vulgaris, drospirenone-containing contraceptives should only be used in women ≥14 years of age who have experienced menarche, desire oral contraception, and do not have any contraindications to oral contraceptives. Off-label uses for this drug include the treatment of menstrual irregularities, dysmenorrhea, hirsutism, and endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Drospirenone inhibits the maturation of follicles and inhibits ovulation, preventing pregnancy. It has antiandrogen effects, improving acne and hirsutism. When combined with ethinyl estradiol, it has been shown to have favorable effects on the plasma lipid profile. Due to its similarity to naturally occurring progesterone, drospirenone is thought to be associated with a lower incidence of progesterone contraceptive related adverse effects, such as breast tenderness and mood swings. A note on venous thromboembolism risk and antimineralcorticoid effects As with other oral contraceptives, the risk of venous thromboembolism and cardiovascular events may be increased when drospirenone is taken. The risk is especially higher in smokers and women aged 35 and older. Women taking this drug should be advised not to smoke. In addition, drospirenone, due to its antimineralcorticoid effects, may increase the risk of hyperkalemia. Patients at high risk for hyperkalemia should not be administered this drug. Consult the official prescribing information for detailed and updated information on the cardiovascular and other risks associated with drospirenone use. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Other changes induced by this drug which may aid in the prevention of pregnancy include alterations in cervical mucus consistency, hindering sperm movement, and lowering the chance of embryo implantation. Drospirenone is an analog of the diuretic spironolactone, which exerts anti-mineralocorticoid activity, blocking aldosterone receptors, which increases sodium and water excretion. Studies in animals have demonstrated that drospirenone administration leads to antiandrogenic activity. This activity helps to oppose the effects of naturally occurring androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptor, and preventing androgen synthesis in the ovaries, helping to treat acne and hirsutism. Drospirenone may also decrease the level of edema in sebaceous follicle during the second half of the menstrual cycle, when acne often appears. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of drospirenone is approximately 76% due to first-pass effects. The maximum plasma concentration of drospirenone occurs within 1 to 2 hours after oral administration and is estimated to range between 60 and 87 ng/mL. A European prescribing monograph for the combination product of estradiol and drospirenone indicates that drospirenone is both completely and rapidly absorbed. It reports a Cmax of 21.9 ng/ml, achieved approximately 1-hour post-administration. The absolute bioavailability is reported to range between 76 to 85%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of drospirenone is estimated to be 4 L/kg, according to the FDA label for Yaz. Prescribing information from a combination of estradiol and drospirenone estimates the volume of distribution to range from 3.7- 4.2 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Drospirenone is about 95% to 97% bound to serum plasma protein, likely to albumin. During in vitro studies, drospirenone was found to bind with low affinity to sex hormone-binding globulin (SHBG). Another reference indicates that drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG), nor corticoid binding globulin (CBG). Only 3-5% of the total drospirenone concentration is measured as a free steroid. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Drospirenone is heavily metabolized. The two major inactive metabolites identified are the acid form of drospirenone produced by the opening of its lactone ring, known as M11, and the 4,5-dihydro-drospirenone-3-sulfate (M14). Drospirenone also undergoes oxidative metabolism via the hepatic cytochrome enzyme CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Various metabolites of drospirenone are measured in the urine and feces. Drospirenone elimination from the body is almost after 10 days post-administration when negligible amounts of drospirenone are found unchanged in both the urine and feces. Between 38% to 47% of the metabolites are identified as glucuronide and sulfate conjugates in the urine. In the feces, approximately 17% to 20% of identifiable metabolites are found to be excreted as glucuronides and sulfates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The serum half-life of drospirenone is estimated to be 30 hours. The half-life of drospirenone metabolite excretion in the urine and feces is approximately 40 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Drospirenone is rapidly cleared, typically within 2-3 days of administration of the last active tablet. The rate of clearance of drospirenone calculated in the serum ranges from 1.2-1.5 ml/min/kg, however, this value can vary by up to 25% according to the patient. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 of drospirenone in rats is >2000 mg/kg. Overdose information An overdose of drospirenone, like other oral contraceptives, may lead to cause nausea or withdrawal bleeding. For drospirenone in particular, as an analog of spironolactone, may affect the levels of serum sodium and potassium. Their concentrations should be monitored in cases of overdose in addition to monitoring from metabolic acidosis and hyperkalemia, which may also result. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Angeliq 0.25/0.5 28 Day, Beyaz 28 Day, Gianvi 28-day, Jasmiel 28 Day, Lo-zumandimine 28 Day, Loryna, Nextstellis 28 Day, Nikki 28 Day, Ocella 28 Day, Safyral 28 Day, Slynd, Syeda 28 Day, Tydemy 28 Day, Vestura, Yasmin, Yasmin 28 Day, Yaz 28 Day, Yaz Plus, Zarah, Zumandimine 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,2-Dihydrospirorenone Dehydrospirorenone Drospirenona Drospirenone Drospirénone Drospirenonum DRSP •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Drospirenone is a progestin used in oral contraceptive pills for the prevention of pregnancy and other conditions. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Duloxetine interact?

•Drug A: Abatacept •Drug B: Duloxetine •Severity: MODERATE •Description: The metabolism of Duloxetine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT 2, 5-HT 3, and α 1 adrenergic receptors. 5-HT 2 and α 1 are both G q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP 3 /PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT 3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2, 5-HT 3, α 1 -adrenergic, and α 2 -adrenergic receptors. 5-HT 2, 5-HT 3, and α 1 -adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT 1 and α 2 receptors are G i /G o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α 1 receptors predominates, vasoconstriction results as the G q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mean of 12 h with a range of 8-17. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdose Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. Carcinogenicity & Mutagenicity Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. Reproductive Toxicity Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). Lactation An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cymbalta, Drizalma, Irenka, Yentreve •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-duloxetine Duloxetina Duloxetine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Duloxetine interact? Information: •Drug A: Abatacept •Drug B: Duloxetine •Severity: MODERATE •Description: The metabolism of Duloxetine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT 2, 5-HT 3, and α 1 adrenergic receptors. 5-HT 2 and α 1 are both G q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP 3 /PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT 3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2, 5-HT 3, α 1 -adrenergic, and α 2 -adrenergic receptors. 5-HT 2, 5-HT 3, and α 1 -adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT 1 and α 2 receptors are G i /G o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α 1 receptors predominates, vasoconstriction results as the G q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mean of 12 h with a range of 8-17. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdose Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. Carcinogenicity & Mutagenicity Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. Reproductive Toxicity Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). Lactation An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cymbalta, Drizalma, Irenka, Yentreve •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-duloxetine Duloxetina Duloxetine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Dutasteride interact?

•Drug A: Abatacept •Drug B: Dutasteride •Severity: MODERATE •Description: The metabolism of Dutasteride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate gland to improve symptoms, and reduce the risk of acute urinary retention and the need for BPH-related surgery alone or in combination with tamsulosin. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dutasteride is a synthetic 4-azasteroid compound that selectively inhibits both the type I and type II isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT). Dutasteride works by reducing the levels of circulating DHT. It was also shown to reduce the size of the prostate gland, improve urinary flow, and symptoms of benign prostatic hyperplasia alone or in combination with tamsulosin. The effect of the reduction of DHT by dutasteride is dose-dependent, with the maximum effect observed within 1-2 weeks following initial administration. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. The serum concentrations of DHT were maintained to be decreased by more than 90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. As evident from the clinical studies, dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT. Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete suppression of serum DHT-more than 90% is seen with dutasteride. By forming a stable complex with both type II and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under in vitro and in vivo conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dutasteride is about 99% bound to albumin and 96.6% bound to α-1 acid glycoprotein in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dutasteride undergoes extensive hepatic metabolism mediated by CYP3A4 and CYP3A5. 4′-hydroxydutasteride, 6-hydroxydutasteride, 6,4′-dihydroxydutasteride, 1,2-dihydrodutasteride, and 15-hydroxydutasteride metabolites are formed. 2 minor metabolites - 6,4′-dihydroxydutasteride and 15-hydroxydutasteride - can also be detected. According to in vitro studies, 4′-hydroxydutasteride and 1,2-dihydrodutasteride mediated inhibitory actions against both isoforms of 5α-reductase but with lower potency when compared to the parent drug. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. This long half-life accounts for the serum concentrations remaining detectable for up to 4 to 6 months after discontinuation of treatment. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In a study of healthy volunteers receiving single oral doses of dutasteride ranging from 0.01 to 40 mg, dutasteride displayed a low linear clearance of 0.58 L/h. The estimated inter-individual variability for the linear clearance was high. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 values The estimated dermal LD50 of dutasteride in rabbits is > 2,000 mg/kg. Overdose In studies of volunteers receiving single doses of dutasteride up to 40 mg (which is 80 times the therapeutic dose) for 7 days, there were no reports of clinically significant adverse events. Low incidences of impotence, reduced libido, gynecomastia, and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients. There are no known antidotes for dutasteride. In case of overdose, appropriate symptomatic and supportive treatment should be given. Nonclinical Toxicology In a 2-year carcinogenicity mouse study, there was an increased incidence of benign hepatocellular adenomas in female mice receiving 250 mg/kg/day. An increased incidence of Leydig cell hyperplasia was observed in male rats receiving doses of 7.5 mg/kg/day and greater. At tumorogenic doses, the luteinizing hormone (LH) levels in rats were increased by 167%. There was no demonstrated a genotoxic potential of dutasteride or its metabolites in a bacterial mutagenesis assay, a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. At much higher doses than the maximum recommended human dose (MRHD) in sexually mature male rats, dutasteride caused a dose- and time-dependent decrease in fertility, reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day), reduced weights of the epididymis, prostate, and seminal vesicles, and microscopic changes in the male reproductive organs. At exposures 425- and 315-fold the expected clinical exposure of dutasteride in rats and dogs, respectively, there were some signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes. Pregnancy and Lactation As DHT is a necessary hormone for the development of male genitalia, exposure to dutasteride in pregnant women bearing male fetuses may cause fetal harm. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Although it is not known whether dutasteride is excreted in human milk, the use of dutasteride in women of childbearing potential, including nursing women. In elderly patients, the half-life of dutasteride may increase. As the renal elimination of dutasteride is very minimal, the use of dutasteride in patients renal insufficiency is reported to be safe. There are no specific dosage adjustment recommendations for use in elderly patients or patients with renal impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avodart, Jalyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dutasterida Dutasteride •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dutasteride is an antiandrogenic compound that is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in adult males by inhibiting 5-alpha reductase.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Dutasteride interact? Information: •Drug A: Abatacept •Drug B: Dutasteride •Severity: MODERATE •Description: The metabolism of Dutasteride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate gland to improve symptoms, and reduce the risk of acute urinary retention and the need for BPH-related surgery alone or in combination with tamsulosin. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Dutasteride is a synthetic 4-azasteroid compound that selectively inhibits both the type I and type II isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT). Dutasteride works by reducing the levels of circulating DHT. It was also shown to reduce the size of the prostate gland, improve urinary flow, and symptoms of benign prostatic hyperplasia alone or in combination with tamsulosin. The effect of the reduction of DHT by dutasteride is dose-dependent, with the maximum effect observed within 1-2 weeks following initial administration. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. The serum concentrations of DHT were maintained to be decreased by more than 90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. As evident from the clinical studies, dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT. Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete suppression of serum DHT-more than 90% is seen with dutasteride. By forming a stable complex with both type II and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under in vitro and in vivo conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dutasteride is about 99% bound to albumin and 96.6% bound to α-1 acid glycoprotein in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dutasteride undergoes extensive hepatic metabolism mediated by CYP3A4 and CYP3A5. 4′-hydroxydutasteride, 6-hydroxydutasteride, 6,4′-dihydroxydutasteride, 1,2-dihydrodutasteride, and 15-hydroxydutasteride metabolites are formed. 2 minor metabolites - 6,4′-dihydroxydutasteride and 15-hydroxydutasteride - can also be detected. According to in vitro studies, 4′-hydroxydutasteride and 1,2-dihydrodutasteride mediated inhibitory actions against both isoforms of 5α-reductase but with lower potency when compared to the parent drug. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. This long half-life accounts for the serum concentrations remaining detectable for up to 4 to 6 months after discontinuation of treatment. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In a study of healthy volunteers receiving single oral doses of dutasteride ranging from 0.01 to 40 mg, dutasteride displayed a low linear clearance of 0.58 L/h. The estimated inter-individual variability for the linear clearance was high. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 values The estimated dermal LD50 of dutasteride in rabbits is > 2,000 mg/kg. Overdose In studies of volunteers receiving single doses of dutasteride up to 40 mg (which is 80 times the therapeutic dose) for 7 days, there were no reports of clinically significant adverse events. Low incidences of impotence, reduced libido, gynecomastia, and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients. There are no known antidotes for dutasteride. In case of overdose, appropriate symptomatic and supportive treatment should be given. Nonclinical Toxicology In a 2-year carcinogenicity mouse study, there was an increased incidence of benign hepatocellular adenomas in female mice receiving 250 mg/kg/day. An increased incidence of Leydig cell hyperplasia was observed in male rats receiving doses of 7.5 mg/kg/day and greater. At tumorogenic doses, the luteinizing hormone (LH) levels in rats were increased by 167%. There was no demonstrated a genotoxic potential of dutasteride or its metabolites in a bacterial mutagenesis assay, a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. At much higher doses than the maximum recommended human dose (MRHD) in sexually mature male rats, dutasteride caused a dose- and time-dependent decrease in fertility, reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day), reduced weights of the epididymis, prostate, and seminal vesicles, and microscopic changes in the male reproductive organs. At exposures 425- and 315-fold the expected clinical exposure of dutasteride in rats and dogs, respectively, there were some signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes. Pregnancy and Lactation As DHT is a necessary hormone for the development of male genitalia, exposure to dutasteride in pregnant women bearing male fetuses may cause fetal harm. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Although it is not known whether dutasteride is excreted in human milk, the use of dutasteride in women of childbearing potential, including nursing women. In elderly patients, the half-life of dutasteride may increase. As the renal elimination of dutasteride is very minimal, the use of dutasteride in patients renal insufficiency is reported to be safe. There are no specific dosage adjustment recommendations for use in elderly patients or patients with renal impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avodart, Jalyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dutasterida Dutasteride •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Dutasteride is an antiandrogenic compound that is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in adult males by inhibiting 5-alpha reductase. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Duvelisib interact?

•Drug A: Abatacept •Drug B: Duvelisib •Severity: MODERATE •Description: The metabolism of Duvelisib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Duvelisib is indicated for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have trialed at least two prior therapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib. In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab. In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K). PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity. The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity. The specific mechanism of this PI3K inhibitors are further described as follows: -BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma. -The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K. -It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells. In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9. The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of duvelisib ranges from 26 to 102 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Duvelesib is mainly metabolized by CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses. From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Copiktra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Duvelisib is an inhibitor of phosphatidylinositol 3-kinase delta and gamma used to treat relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Duvelisib interact? Information: •Drug A: Abatacept •Drug B: Duvelisib •Severity: MODERATE •Description: The metabolism of Duvelisib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Duvelisib is indicated for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have trialed at least two prior therapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib. In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab. In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K). PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity. The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity. The specific mechanism of this PI3K inhibitors are further described as follows: -BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma. -The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K. -It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells. In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9. The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of duvelisib ranges from 26 to 102 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Duvelesib is mainly metabolized by CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses. From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Copiktra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Duvelisib is an inhibitor of phosphatidylinositol 3-kinase delta and gamma used to treat relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Ebastine interact?

•Drug A: Abatacept •Drug B: Ebastine •Severity: MODERATE •Description: The metabolism of Ebastine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ebastine is a second generation H1-receptor antagonist useful in the treatment of allergic rhinitis and urticaria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ebastine interact? Information: •Drug A: Abatacept •Drug B: Ebastine •Severity: MODERATE •Description: The metabolism of Ebastine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ebastine is a second generation H1-receptor antagonist useful in the treatment of allergic rhinitis and urticaria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Ebola Zaire vaccine (live, attenuated) interact?

•Drug A: Abatacept •Drug B: Ebola Zaire vaccine (live, attenuated) •Severity: MODERATE •Description: The therapeutic efficacy of Ebola Zaire vaccine (live, attenuated) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Ebola Zaire vaccine (live, attenuated) interact? Information: •Drug A: Abatacept •Drug B: Ebola Zaire vaccine (live, attenuated) •Severity: MODERATE •Description: The therapeutic efficacy of Ebola Zaire vaccine (live, attenuated) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Eculizumab interact?

•Drug A: Abatacept •Drug B: Eculizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Eculizumab is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eculizumab is indicated in the US to treat paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy, and neuromyelitis optica spectrum disorder (NMOSD). It is also indicated in EU to treat PNH in both adult and pediatric patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eculizumab is a monoclonal antibody that prevents the activation of terminal complement in some autoimmune conditions. Eculizumab has a long duration of action. Patients taking this medication should be vaccinated against Neisseria meningiditis as serious meningococcal infections have occurred in the past. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eculizumab is a monoclonal antibody that targets complement protein C5, preventing cleavage to C5a and C5b, and the formation of the terminal complement complex C5b-9. Inhibition of this complex prevents complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobunuria, complement mediated microangiopathy in atypical hemolytic uremic syndrome, and immune mediated inflammation and damage of the central nervous system in neuromyelitis optica spectrum disorder. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eculizumab is administered by intravenous infusion so the bioavailability is 100%. This drug reaches a C max of 194±76µg/mL and C trough of 97±60µg/mL. The AUC was calculated to be 24,467.6µg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of eculizumab is 5-8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Though protein binding data is scarce, eculizumab is unlikely to be protein bound as it is a monoclonal antibody. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eculizumab is a monoclonal antibody and is expected to be metabolized to small peptides and amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Monoclonal antibodies are not eliminated in the urine, and only a small amount is excreted in bile. Most monoclonal antibodies are catabolized in lysosomes to amino acids. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of eculizumab is 270-375h or 272±82h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Pharmacokinetic properties in healthy patients have not been determined. In patients with rhematoid arthritis, there is an average clearance of 0.26mL/kg/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdoses of eculizumab are unlikely as it is administered under specialist supervision. In case of overdose, contact local poison control. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Soliris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eculizumab is a recombinant humanized monoclonal antibody used to reduce the risk of hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Eculizumab interact? Information: •Drug A: Abatacept •Drug B: Eculizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Eculizumab is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eculizumab is indicated in the US to treat paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy, and neuromyelitis optica spectrum disorder (NMOSD). It is also indicated in EU to treat PNH in both adult and pediatric patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eculizumab is a monoclonal antibody that prevents the activation of terminal complement in some autoimmune conditions. Eculizumab has a long duration of action. Patients taking this medication should be vaccinated against Neisseria meningiditis as serious meningococcal infections have occurred in the past. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eculizumab is a monoclonal antibody that targets complement protein C5, preventing cleavage to C5a and C5b, and the formation of the terminal complement complex C5b-9. Inhibition of this complex prevents complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobunuria, complement mediated microangiopathy in atypical hemolytic uremic syndrome, and immune mediated inflammation and damage of the central nervous system in neuromyelitis optica spectrum disorder. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eculizumab is administered by intravenous infusion so the bioavailability is 100%. This drug reaches a C max of 194±76µg/mL and C trough of 97±60µg/mL. The AUC was calculated to be 24,467.6µg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of eculizumab is 5-8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Though protein binding data is scarce, eculizumab is unlikely to be protein bound as it is a monoclonal antibody. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eculizumab is a monoclonal antibody and is expected to be metabolized to small peptides and amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Monoclonal antibodies are not eliminated in the urine, and only a small amount is excreted in bile. Most monoclonal antibodies are catabolized in lysosomes to amino acids. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of eculizumab is 270-375h or 272±82h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Pharmacokinetic properties in healthy patients have not been determined. In patients with rhematoid arthritis, there is an average clearance of 0.26mL/kg/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdoses of eculizumab are unlikely as it is administered under specialist supervision. In case of overdose, contact local poison control. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Soliris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eculizumab is a recombinant humanized monoclonal antibody used to reduce the risk of hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Efavirenz interact?

•Drug A: Abatacept •Drug B: Efavirenz •Severity: MODERATE •Description: The metabolism of Efavirenz can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use in combination treatment of HIV infection (AIDS) •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99.5-99.75% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 40-55 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atripla, Stocrin, Sustiva, Symfi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Efavirenz Éfavirenz Efavirenzum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Efavirenz is a non-nucleoside reverse transcriptase inhibitor used to treat HIV infection or prevent the spread of HIV.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Efavirenz interact? Information: •Drug A: Abatacept •Drug B: Efavirenz •Severity: MODERATE •Description: The metabolism of Efavirenz can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use in combination treatment of HIV infection (AIDS) •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99.5-99.75% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 40-55 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atripla, Stocrin, Sustiva, Symfi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Efavirenz Éfavirenz Efavirenzum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Efavirenz is a non-nucleoside reverse transcriptase inhibitor used to treat HIV infection or prevent the spread of HIV. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Efgartigimod alfa interact?

•Drug A: Abatacept •Drug B: Efgartigimod alfa •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Efgartigimod alfa. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Efgartigimod alfa - delivered intravenously as a monotherapy or subcutaneously in combination with recombinant human hyaluronidase - is indicated for the treatment of generalized myasthenia gravis in adult patients who are anti-acetylcholine receptor antibody-positive. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Efgartigimod alfa exerts its pharmacologic effect by reducing circulating levels of the autoantibody responsible for myasthenia gravis symptoms. It is administered as a once-weekly intravenous or subcutaneous infusion, given for 4 weeks per treatment cycle, with the option to initiate additional treatment cycles as clinically indicated after at least 50 days have passed following the previous cycle. Because efgartigimod alfa reduces circulating IgG levels, patients undergoing therapy may be at greater risk of infection due to a depressed immune response. It should not be initiated in patients with an active infection, and consideration should be given to holding therapy in patients who develop a serious infection during a treatment cycle. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction of the skeletal muscles. While the pathophysiologic mechanisms of MG differ depending on the subtype in question, all forms involve the production of IgG autoantibodies to some endogenous protein. One of the most commonly implicated proteins against which autoantibodies are produced are acetylcholine receptors (AChRs), which undergo degradation via the membrane attack complex (MAC) secondary to their interaction with AChR-specific autoantibodies. The destruction of AChRs prevents regular transmission of electrical impulses across the neuromuscular junction, which ultimately leads to the characteristic muscular weakness - especially of the eyes, throat, and extremities - observed in patients with MG. Immunoglobulin G, as opposed to other immunoglobulins, undergoes a recycling phase in the vascular endothelium that dramatically extends its half-life. In the case of pathogenic IgGs causing MG, this may facilitate an increased ability to impair neuromuscular transmission. This recycling involves IgG binding to the neonatal Fc receptor (FcRn), which rescues IgG from lysosomal degradation. Efgartigimod alfa is a human IgG1 antibody fragment that binds to FcRn, thus preventing IgG recycling and subsequently reducing the amount of circulating IgG, including the autoantibodies responsible for MG. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of efgartigimod alfa ranges from 15 to 20 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other therapeutic proteins, efgartigimod alfa is likely metabolized to smaller peptides and amino acids via proteolytic enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single intravenous dose of efgartigimod alfa 10 mg/kg in healthy subjects, less than 0.1% of the administered dose was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of efgartigimod alfa ranges from 80 to 120 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There are no data regarding overdosage with efgartigimod alfa. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Vyvgart, Vyvgart Hytrulo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Efgartigimod alfa is a neonatal Fc receptor blocker used to treat generalized myasthenia gravis in patients who are AChR-antibody positive.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Efgartigimod alfa interact? Information: •Drug A: Abatacept •Drug B: Efgartigimod alfa •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Efgartigimod alfa. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Efgartigimod alfa - delivered intravenously as a monotherapy or subcutaneously in combination with recombinant human hyaluronidase - is indicated for the treatment of generalized myasthenia gravis in adult patients who are anti-acetylcholine receptor antibody-positive. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Efgartigimod alfa exerts its pharmacologic effect by reducing circulating levels of the autoantibody responsible for myasthenia gravis symptoms. It is administered as a once-weekly intravenous or subcutaneous infusion, given for 4 weeks per treatment cycle, with the option to initiate additional treatment cycles as clinically indicated after at least 50 days have passed following the previous cycle. Because efgartigimod alfa reduces circulating IgG levels, patients undergoing therapy may be at greater risk of infection due to a depressed immune response. It should not be initiated in patients with an active infection, and consideration should be given to holding therapy in patients who develop a serious infection during a treatment cycle. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction of the skeletal muscles. While the pathophysiologic mechanisms of MG differ depending on the subtype in question, all forms involve the production of IgG autoantibodies to some endogenous protein. One of the most commonly implicated proteins against which autoantibodies are produced are acetylcholine receptors (AChRs), which undergo degradation via the membrane attack complex (MAC) secondary to their interaction with AChR-specific autoantibodies. The destruction of AChRs prevents regular transmission of electrical impulses across the neuromuscular junction, which ultimately leads to the characteristic muscular weakness - especially of the eyes, throat, and extremities - observed in patients with MG. Immunoglobulin G, as opposed to other immunoglobulins, undergoes a recycling phase in the vascular endothelium that dramatically extends its half-life. In the case of pathogenic IgGs causing MG, this may facilitate an increased ability to impair neuromuscular transmission. This recycling involves IgG binding to the neonatal Fc receptor (FcRn), which rescues IgG from lysosomal degradation. Efgartigimod alfa is a human IgG1 antibody fragment that binds to FcRn, thus preventing IgG recycling and subsequently reducing the amount of circulating IgG, including the autoantibodies responsible for MG. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of efgartigimod alfa ranges from 15 to 20 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other therapeutic proteins, efgartigimod alfa is likely metabolized to smaller peptides and amino acids via proteolytic enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single intravenous dose of efgartigimod alfa 10 mg/kg in healthy subjects, less than 0.1% of the administered dose was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of efgartigimod alfa ranges from 80 to 120 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There are no data regarding overdosage with efgartigimod alfa. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Vyvgart, Vyvgart Hytrulo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Efgartigimod alfa is a neonatal Fc receptor blocker used to treat generalized myasthenia gravis in patients who are AChR-antibody positive. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Elagolix interact?

•Drug A: Abatacept •Drug B: Elagolix •Severity: MODERATE •Description: The metabolism of Elagolix can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): During a three menstrual cycle study in healthy women, an elagolix 150 mg once daily regimen and a 200 mg twice daily regimen resulted in an ovulation rate of about 50% and 32%, respectively. In Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for the 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Furthermore, the effect of elagolix on the QTc interval was investigated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects administered a single dose of 1200 mg was seventeen times higher than the concentration in subjects given elagolix 200 mg twice daily. Nevertheless, there was no clinically relevant prolongation of the QTc interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Endometriosis develops when tissue that is similar to the kind that is normally located in the uterus starts to grow outside of the uterus. Such growth leads to various symptoms like pain during periods, pelvic pain between periods, and pain during sexual intercourse. The growths themselves are referred to as lesions and frequently develop on the ovaries, fallopian tubes, and other areas around the uterus, including the bowel or bladder. The growth of these lesions is dependent upon the estrogen hormone. Elagolix is an orally-administered, nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The Tmax of elagolix is reported as being 1.0 hours. The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The percentage bound to human plasma proteins for elagolix has been documented as 80%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Elagolix is predominantly metabolized by the CYP3A family of isoenzymes despite participating in minor metabolic pathways with the CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) enzymes as well. The primary metabolite of elagolix, referred to as NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino}-butyrate), is not believed to possess any significant biologic activity due to its low plasma exposure and an observed potency that is exceptionally less than the parent elagolix compound (Ki value of 3.5 compared to 0.9 nM). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The primary route of elimination of elagolix is via hepatic metabolism. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal phase elimination half-life of elagolix is recorded as being 4 to 6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed. Common adverse reactions of elagolix include hot flush, headache, nausea, insomnia, mood alterations, amenorrhea, depression, anxiety, arthralgia, bone loss, changes in menstrual bleeding patterns, suicidal ideation and behavior, exacerbation of existing mood disorders, and/or hepatic transaminase elevations. The recommended duration of use for elagolix is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Oriahnn 28 Day Kit, Orilissa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Elagolix is a gonadotropin releasing hormone receptor antagonist used to treat moderate to severe pain in endometriosis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Elagolix interact? Information: •Drug A: Abatacept •Drug B: Elagolix •Severity: MODERATE •Description: The metabolism of Elagolix can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): During a three menstrual cycle study in healthy women, an elagolix 150 mg once daily regimen and a 200 mg twice daily regimen resulted in an ovulation rate of about 50% and 32%, respectively. In Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for the 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Furthermore, the effect of elagolix on the QTc interval was investigated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects administered a single dose of 1200 mg was seventeen times higher than the concentration in subjects given elagolix 200 mg twice daily. Nevertheless, there was no clinically relevant prolongation of the QTc interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Endometriosis develops when tissue that is similar to the kind that is normally located in the uterus starts to grow outside of the uterus. Such growth leads to various symptoms like pain during periods, pelvic pain between periods, and pain during sexual intercourse. The growths themselves are referred to as lesions and frequently develop on the ovaries, fallopian tubes, and other areas around the uterus, including the bowel or bladder. The growth of these lesions is dependent upon the estrogen hormone. Elagolix is an orally-administered, nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The Tmax of elagolix is reported as being 1.0 hours. The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The percentage bound to human plasma proteins for elagolix has been documented as 80%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Elagolix is predominantly metabolized by the CYP3A family of isoenzymes despite participating in minor metabolic pathways with the CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) enzymes as well. The primary metabolite of elagolix, referred to as NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino}-butyrate), is not believed to possess any significant biologic activity due to its low plasma exposure and an observed potency that is exceptionally less than the parent elagolix compound (Ki value of 3.5 compared to 0.9 nM). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The primary route of elimination of elagolix is via hepatic metabolism. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal phase elimination half-life of elagolix is recorded as being 4 to 6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed. Common adverse reactions of elagolix include hot flush, headache, nausea, insomnia, mood alterations, amenorrhea, depression, anxiety, arthralgia, bone loss, changes in menstrual bleeding patterns, suicidal ideation and behavior, exacerbation of existing mood disorders, and/or hepatic transaminase elevations. The recommended duration of use for elagolix is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Oriahnn 28 Day Kit, Orilissa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Elagolix is a gonadotropin releasing hormone receptor antagonist used to treat moderate to severe pain in endometriosis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Eletriptan interact?

•Drug A: Abatacept •Drug B: Eletriptan •Severity: MODERATE •Description: The metabolism of Eletriptan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the acute treatment of migraine with or without aura in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eletriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist. In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors, and little or no affinity for 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT6 receptors. In contrast, eletriptan displays insignificant pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors. While the full mechanism of action of 5-HT receptor agonists in relieving migrains is not fully elucidated, it is proposed that the activation of 5-HT1 receptors located on intracranial blood vessels leads to vasoconstriction that correlates with the relief of migraine headaches. It is also proposed that the activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system leads to the inhibition of release of pro-inflammatory neuropeptides. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed after oral administration with a mean absolute bioavailability of approximately 50%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 138 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is moderate and approximately 85%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. The N-demethylated metabolite of eletriptan is the only known active metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of eletriptan is approximately 4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal cl=3.9 L/h •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on the pharmacology of the 5-HT1B/1D agonists, hypertension or other more serious cardiovascular symptoms could occur on overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Relpax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eletriptan is a triptan used for the treatment of migraines.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Eletriptan interact? Information: •Drug A: Abatacept •Drug B: Eletriptan •Severity: MODERATE •Description: The metabolism of Eletriptan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the acute treatment of migraine with or without aura in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eletriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist. In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors, and little or no affinity for 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT6 receptors. In contrast, eletriptan displays insignificant pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors. While the full mechanism of action of 5-HT receptor agonists in relieving migrains is not fully elucidated, it is proposed that the activation of 5-HT1 receptors located on intracranial blood vessels leads to vasoconstriction that correlates with the relief of migraine headaches. It is also proposed that the activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system leads to the inhibition of release of pro-inflammatory neuropeptides. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed after oral administration with a mean absolute bioavailability of approximately 50%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 138 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is moderate and approximately 85%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. The N-demethylated metabolite of eletriptan is the only known active metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life of eletriptan is approximately 4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal cl=3.9 L/h •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on the pharmacology of the 5-HT1B/1D agonists, hypertension or other more serious cardiovascular symptoms could occur on overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Relpax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eletriptan is a triptan used for the treatment of migraines. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Eliglustat interact?

•Drug A: Abatacept •Drug B: Eliglustat •Severity: MODERATE •Description: The metabolism of Eliglustat can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eliglustat is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease in adult patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. CYP2D6 ultra-rapid metabolizers may not achieve adequate eliglustat concentrations to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eliglustat is a specific inhibitor of glucosylceramide synthase (IC 50 =10 ng/mL). In vitro studies suggest that eliglustat has minimal or no off-target activity against other glycosidases, such as α-glucosidase I and II, and lysosomal and non-lysosomal glucosylceramidases. At 8 times the recommended dose (800 mg) and a ​​mean peak concentration of 237 ng/mL, eliglustat did not have a clinically significant effect on QTc prolongation. However, modelling of PK/PD data predicts that at a plasma concentration of 500 ng/mL, PR, QRS and QTcF intervals increase 22, 7, and 13 msec, respectively. Since high plasma concentrations of eliglustat may increase the risk of cardiac arrhythmias, there are warnings and precautions for patients taking CYP2D6 or CYP3A4 inhibitors, those with specific CYP2D6 metabolizer status and different degrees of hepatic impairment. Depending on each case, the use of this drug is contraindicated, to be avoided, or requires dosage adjustment. Patients with preexisting cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or those taking Class IA or Class II antiarrhythmic drugs are advised to avoid eliglustat. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eliglustat is a glucosylceramide synthase inhibitor used for the treatment of type 1 Gaucher disease. Gaucher disease is a rare genetic disorder characterized by the deficiency of acid β-glucosidase, an enzyme that converts glucosylceramide (also known as glucocerebroside) into glucose and ceramide. In patients with Gaucher disease, glucosylceramide is accumulated in the lysosomes of macrophages, leading to the formation of foam cells or Gaucher cells. Gaucher cells infiltrate the liver, spleen, bone marrow and other organs, leading to complications such as anemia, thrombocytopenia and hepatosplenomegaly. Eliglustat reduces the production of glucosylceramide by inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids. This lowers the amount of glucosylceramide that is available in lysosomes, and balances the deficiency of acid β-glucosidase. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eliglustat administered in multiple doses of 84 mg twice daily had a C max of 12.1 to 25.0 ng/mL in CYP2D6 extensive metabolizers (EMs), 44.6 ng/mL in CYP2D6 intermediate metabolizers (IMs), and 113 to 137 ng/mL in CYP2D6 poor metabolizers (PMs). The median T max was 1.5-2 hr in CYP2D6 EMs, 2 hr in CYP2D6 IMs, and 3 hr in CYP2D6 PMs. The AUC tau was 76.3-143 ng∙hr/mL in CYP2D6 EMs, 306 ng∙hr/mL in CYP2D6 IMs, and 922-1057 ng∙hr/mL in CYP2D6 PMs. In CYP2D6 EMs, the pharmacokinetics of eliglustat is time-dependent, and for doses that range between 42 and 294 mg, exposure increases in a more than dose-proportional fashion. In CYP2D6 PMs, eliglustat pharmacokinetics is linear and time-independent. In a steady state, the systemic exposure of 84 mg eliglustat twice daily is 7- to 9-fold higher in CYP2D6 PMs compared to EMs. Following the oral administration of a single 84 mg dose of eliglustat, bioavailability in CYP2D6 EMs was lower than 5%. The low oral bioavailability of eliglustat suggests the role of transporters and/or an extensive first-pass metabolism. Eliglustat can be taken with or without food. In CYP2D6 EMs, severe renal impairment did not have an effect on eliglustat pharmacokinetics. The effect of renal impairment on eliglustat pharmacokinetics was not evaluated in CYP2D6 IMs, CYP2D6 PMs or CYP2D6 EMs with end-stage renal failure. Compared to CYP2D6 EMs with normal hepatic function, C max and AUC were 1.2-fold higher in CYP2D6 EMs with mild hepatic impairment, while C max and AUC were 2.8- and 5.2-fold higher, respectively, in CYP2D6 EMs with moderate hepatic impairment. The effect of mild and moderate hepatic impairment in CYP2D6 IMs and PMs, and the effect of severe hepatic impairment were not evaluated. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In CYP2D6 extensive metabolizers (EM), the volume of distribution of eliglustat administered IV was 835 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In plasma, the protein binding of eliglustat goes from 76% to 83%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eliglustat is mostly metabolized by CYP2D6, and to a lower extent, by CYP3A4. In patients that are CYP2D6 poor metabolizers (PMs), eliglustat is mainly metabolized by CYP3A4. The primary metabolic pathways of eliglustat involve the sequential oxidation of the octanoyl moiety and the 2,3-dihydro-1,4-benzodioxane moiety. The combination of these two pathways results in the production of several oxidative metabolites. After evaluating the potency of eliglustat metabolites, it was determined that none of them were active. Genz-399240 (M24) was identified as the major metabolite of eliglustat, while the rest of the metabolites contributed to less than 10% of total drug-related exposures. Genz-399240 (M24) did not show any major off-target effects; therefore, a transporter substrate specificity characterization was not performed. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eliglustat is mainly excreted in urine (42%) and feces (51%) as metabolites after oral administration. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Eliglustat has a terminal elimination half-life of 6.5 hours in CYP2D6 extensive metabolizers (EMs) and 8.9 h in CYP2D6 poor metabolizers (PMs). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy CYP2D6 extensive metabolizers (EMs) administered 42 mg of eliglustat IV (0.5 times the recommended oral dose), clearance was 88 L/h (80-105 L/h). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Eliglustat overdose may manifest as dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. These symptoms were detected in a healthy subject taking 21-times the dose recommended to type 1 Gaucher disease patients. Eliglustat has no known antidote. In case of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. Due to the large volume of distribution of eliglustat, hemodialysis is not likely to be beneficial. Acute dose toxicity studies were performed in rats and dogs. In rats, the maximum tolerated dose was 200 mg/kg, and in non-fasted dogs, the maximum tolerated dose was 25 mg/kg. Some of the adverse effects detected in these toxicity studies manifested on the GI tract, hematology parameters related to hemoglobin and coagulation process, reproductive organs, thymus and other lymphoid organs. Adverse effects in the kidney and liver were only detected in rats. Carcinogenic studies were performed in both Sprague-Dawley rats and CD-1 mice. In doses up to 50 mg/kg/day in female Sprague-Dawley rats and 75 mg/kg/day in male Sprague-Dawley rats and CD-1 mice, eliglustat did not induce neoplasms. Eliglustat was negative in the following mutagenesis tests: Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cerdelga •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Eliglustat éliglustat Eliglustatum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Eliglustat interact? Information: •Drug A: Abatacept •Drug B: Eliglustat •Severity: MODERATE •Description: The metabolism of Eliglustat can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eliglustat is a glucosylceramide synthase inhibitor indicated for the long-term treatment of type 1 Gaucher disease in adult patients who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. CYP2D6 ultra-rapid metabolizers may not achieve adequate eliglustat concentrations to achieve a therapeutic effect. A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eliglustat is a specific inhibitor of glucosylceramide synthase (IC 50 =10 ng/mL). In vitro studies suggest that eliglustat has minimal or no off-target activity against other glycosidases, such as α-glucosidase I and II, and lysosomal and non-lysosomal glucosylceramidases. At 8 times the recommended dose (800 mg) and a ​​mean peak concentration of 237 ng/mL, eliglustat did not have a clinically significant effect on QTc prolongation. However, modelling of PK/PD data predicts that at a plasma concentration of 500 ng/mL, PR, QRS and QTcF intervals increase 22, 7, and 13 msec, respectively. Since high plasma concentrations of eliglustat may increase the risk of cardiac arrhythmias, there are warnings and precautions for patients taking CYP2D6 or CYP3A4 inhibitors, those with specific CYP2D6 metabolizer status and different degrees of hepatic impairment. Depending on each case, the use of this drug is contraindicated, to be avoided, or requires dosage adjustment. Patients with preexisting cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or those taking Class IA or Class II antiarrhythmic drugs are advised to avoid eliglustat. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eliglustat is a glucosylceramide synthase inhibitor used for the treatment of type 1 Gaucher disease. Gaucher disease is a rare genetic disorder characterized by the deficiency of acid β-glucosidase, an enzyme that converts glucosylceramide (also known as glucocerebroside) into glucose and ceramide. In patients with Gaucher disease, glucosylceramide is accumulated in the lysosomes of macrophages, leading to the formation of foam cells or Gaucher cells. Gaucher cells infiltrate the liver, spleen, bone marrow and other organs, leading to complications such as anemia, thrombocytopenia and hepatosplenomegaly. Eliglustat reduces the production of glucosylceramide by inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids. This lowers the amount of glucosylceramide that is available in lysosomes, and balances the deficiency of acid β-glucosidase. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eliglustat administered in multiple doses of 84 mg twice daily had a C max of 12.1 to 25.0 ng/mL in CYP2D6 extensive metabolizers (EMs), 44.6 ng/mL in CYP2D6 intermediate metabolizers (IMs), and 113 to 137 ng/mL in CYP2D6 poor metabolizers (PMs). The median T max was 1.5-2 hr in CYP2D6 EMs, 2 hr in CYP2D6 IMs, and 3 hr in CYP2D6 PMs. The AUC tau was 76.3-143 ng∙hr/mL in CYP2D6 EMs, 306 ng∙hr/mL in CYP2D6 IMs, and 922-1057 ng∙hr/mL in CYP2D6 PMs. In CYP2D6 EMs, the pharmacokinetics of eliglustat is time-dependent, and for doses that range between 42 and 294 mg, exposure increases in a more than dose-proportional fashion. In CYP2D6 PMs, eliglustat pharmacokinetics is linear and time-independent. In a steady state, the systemic exposure of 84 mg eliglustat twice daily is 7- to 9-fold higher in CYP2D6 PMs compared to EMs. Following the oral administration of a single 84 mg dose of eliglustat, bioavailability in CYP2D6 EMs was lower than 5%. The low oral bioavailability of eliglustat suggests the role of transporters and/or an extensive first-pass metabolism. Eliglustat can be taken with or without food. In CYP2D6 EMs, severe renal impairment did not have an effect on eliglustat pharmacokinetics. The effect of renal impairment on eliglustat pharmacokinetics was not evaluated in CYP2D6 IMs, CYP2D6 PMs or CYP2D6 EMs with end-stage renal failure. Compared to CYP2D6 EMs with normal hepatic function, C max and AUC were 1.2-fold higher in CYP2D6 EMs with mild hepatic impairment, while C max and AUC were 2.8- and 5.2-fold higher, respectively, in CYP2D6 EMs with moderate hepatic impairment. The effect of mild and moderate hepatic impairment in CYP2D6 IMs and PMs, and the effect of severe hepatic impairment were not evaluated. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In CYP2D6 extensive metabolizers (EM), the volume of distribution of eliglustat administered IV was 835 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In plasma, the protein binding of eliglustat goes from 76% to 83%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eliglustat is mostly metabolized by CYP2D6, and to a lower extent, by CYP3A4. In patients that are CYP2D6 poor metabolizers (PMs), eliglustat is mainly metabolized by CYP3A4. The primary metabolic pathways of eliglustat involve the sequential oxidation of the octanoyl moiety and the 2,3-dihydro-1,4-benzodioxane moiety. The combination of these two pathways results in the production of several oxidative metabolites. After evaluating the potency of eliglustat metabolites, it was determined that none of them were active. Genz-399240 (M24) was identified as the major metabolite of eliglustat, while the rest of the metabolites contributed to less than 10% of total drug-related exposures. Genz-399240 (M24) did not show any major off-target effects; therefore, a transporter substrate specificity characterization was not performed. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eliglustat is mainly excreted in urine (42%) and feces (51%) as metabolites after oral administration. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Eliglustat has a terminal elimination half-life of 6.5 hours in CYP2D6 extensive metabolizers (EMs) and 8.9 h in CYP2D6 poor metabolizers (PMs). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy CYP2D6 extensive metabolizers (EMs) administered 42 mg of eliglustat IV (0.5 times the recommended oral dose), clearance was 88 L/h (80-105 L/h). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Eliglustat overdose may manifest as dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. These symptoms were detected in a healthy subject taking 21-times the dose recommended to type 1 Gaucher disease patients. Eliglustat has no known antidote. In case of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. Due to the large volume of distribution of eliglustat, hemodialysis is not likely to be beneficial. Acute dose toxicity studies were performed in rats and dogs. In rats, the maximum tolerated dose was 200 mg/kg, and in non-fasted dogs, the maximum tolerated dose was 25 mg/kg. Some of the adverse effects detected in these toxicity studies manifested on the GI tract, hematology parameters related to hemoglobin and coagulation process, reproductive organs, thymus and other lymphoid organs. Adverse effects in the kidney and liver were only detected in rats. Carcinogenic studies were performed in both Sprague-Dawley rats and CD-1 mice. In doses up to 50 mg/kg/day in female Sprague-Dawley rats and 75 mg/kg/day in male Sprague-Dawley rats and CD-1 mice, eliglustat did not induce neoplasms. Eliglustat was negative in the following mutagenesis tests: Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cerdelga •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Eliglustat éliglustat Eliglustatum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eliglustat is a glucosylceramide synthase used to treat type 1 Gaucher disease in patients who are CYP2D6 extensive, intermediate, or poor metabolizers. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Eltrombopag interact?

•Drug A: Abatacept •Drug B: Eltrombopag •Severity: MODERATE •Description: The metabolism of Eltrombopag can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Eltrombopag is highly protein bound (>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alvaiz, Promacta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eltrombopag is a thrombopoietin receptor agonist used to treat thrombocytopenia or aplastic anemia associated with various etiologies.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Eltrombopag interact? Information: •Drug A: Abatacept •Drug B: Eltrombopag •Severity: MODERATE •Description: The metabolism of Eltrombopag can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Eltrombopag is highly protein bound (>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alvaiz, Promacta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eltrombopag is a thrombopoietin receptor agonist used to treat thrombocytopenia or aplastic anemia associated with various etiologies. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Emapalumab interact?

•Drug A: Abatacept •Drug B: Emapalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Emapalumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Emapalumab is indicated for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. The HLH condition is a hyperinflammatory status characterized by the overwhelming activation of normal T lymphocytes and macrophages which can lead to disturbances in the hematology profile and even death. As part of the condition profile, there have been reports proving a massive overexpression of interferon-gamma which is thought to drive the immune hyperactivation leading to organ failure. This condition is usually developed and present the symptomatic profile within the first months or years of life. These symptoms consist of fever, enlarged liver or spleen and a lower number of blood cells. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In phase 2/3 clinical trials, emapalumab administered concomitantly with dexamethasone reported an overall response in 63% of the patients. The overall response was defined as achievement of a complete or partial response or HLH improvement. In this trial and as a proof of interferon-gamma neutralization, there was registered a sharp decrease in serum CXCL9 and to avoid QT prolongation in the presence of low doses of emapalumab. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Emapalumab acts by binding and neutralizing interferon-gamma. The specific interaction between emapalumab and interferon-gamma produces an inhibition in the interaction between interferon-gamma and its cognate receptor on T-cells which produces the neutralizing activity. It is important to consider that emapalumab inhibits both free and IFNGR1-bound interferon-gamma as well as the interaction with IFNGR1 and IFNGR2 at the cell surface. HLH is an immune dysregulation syndrome in which several cytokines are involved but it has been reported that interferon-gamma plays a pivotal role in the development of this disease as studies have shown a vast increase in the interferon-gamma levels in HLH patients. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In clinical pharmacokinetic studies, a dose of 1 mg/kg of emapalumab was administered which generated a peak concentration at steady state of 44 mcg/ml and a median steady-state concentration of 25 mcg/ml. The serum concentration of emapalumab increases proportionally between a dose of 1-3 mg/kg and the steady-state is attained by the 7th infusion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The central and peripheral volume of distribution of emapalumab are 4.2 and 5.6 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are usually not required to have protein binding studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling. Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Emapalumab presents a target-mediated clearance that is dependent on interferon-gamma production. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Emapalumab elimination half-life is of approximately 22 days in healthy subjects and it ranges between 2.5-18.9 in HLH patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Emapalumab clearance is reported to be 0.007 L/h in healthy subjects. This clearance rate can vary in HLH patients depending on the production of interferon-gamma. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There are no reported effects in male or female reproductive organs after an 8- or 13-week repeat-dose toxicity study in animals. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gamifant •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Emapalumab is an interferon gamma blocking antibody used to treat primary hemophagocytic lymphohistiocytosis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Emapalumab interact? Information: •Drug A: Abatacept •Drug B: Emapalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Emapalumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Emapalumab is indicated for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. The HLH condition is a hyperinflammatory status characterized by the overwhelming activation of normal T lymphocytes and macrophages which can lead to disturbances in the hematology profile and even death. As part of the condition profile, there have been reports proving a massive overexpression of interferon-gamma which is thought to drive the immune hyperactivation leading to organ failure. This condition is usually developed and present the symptomatic profile within the first months or years of life. These symptoms consist of fever, enlarged liver or spleen and a lower number of blood cells. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In phase 2/3 clinical trials, emapalumab administered concomitantly with dexamethasone reported an overall response in 63% of the patients. The overall response was defined as achievement of a complete or partial response or HLH improvement. In this trial and as a proof of interferon-gamma neutralization, there was registered a sharp decrease in serum CXCL9 and to avoid QT prolongation in the presence of low doses of emapalumab. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Emapalumab acts by binding and neutralizing interferon-gamma. The specific interaction between emapalumab and interferon-gamma produces an inhibition in the interaction between interferon-gamma and its cognate receptor on T-cells which produces the neutralizing activity. It is important to consider that emapalumab inhibits both free and IFNGR1-bound interferon-gamma as well as the interaction with IFNGR1 and IFNGR2 at the cell surface. HLH is an immune dysregulation syndrome in which several cytokines are involved but it has been reported that interferon-gamma plays a pivotal role in the development of this disease as studies have shown a vast increase in the interferon-gamma levels in HLH patients. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In clinical pharmacokinetic studies, a dose of 1 mg/kg of emapalumab was administered which generated a peak concentration at steady state of 44 mcg/ml and a median steady-state concentration of 25 mcg/ml. The serum concentration of emapalumab increases proportionally between a dose of 1-3 mg/kg and the steady-state is attained by the 7th infusion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The central and peripheral volume of distribution of emapalumab are 4.2 and 5.6 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are usually not required to have protein binding studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling. Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Emapalumab presents a target-mediated clearance that is dependent on interferon-gamma production. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Emapalumab elimination half-life is of approximately 22 days in healthy subjects and it ranges between 2.5-18.9 in HLH patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Emapalumab clearance is reported to be 0.007 L/h in healthy subjects. This clearance rate can vary in HLH patients depending on the production of interferon-gamma. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There are no reported effects in male or female reproductive organs after an 8- or 13-week repeat-dose toxicity study in animals. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gamifant •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Emapalumab is an interferon gamma blocking antibody used to treat primary hemophagocytic lymphohistiocytosis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Enasidenib interact?

•Drug A: Abatacept •Drug B: Enasidenib •Severity: MAJOR •Description: The metabolism of Enasidenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts, and increased percentages of mature myeloid cells. In a study involving adult patients with relapsed or refractory AML, an overall response rate of 40.3% was achieved in enasidenib therapy, which was associated with cellular differentiation and maturation without evidence of aplasia. The potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. No large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Enasidenib is a selective inhibitor of IDH2, a mitochondria-localized enzyme involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. Wild-type IDH proteins play a cruicial role in the Krebs/citric acid cycle where it catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. In comparison, mutant forms of IDH2 enzyme mediates a neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked cellular differentiation of hematopoietic progenitor cells. Enasidenib primarily targets the mutant IDH2 variants R140Q, R172S, and R172K with higher potency than the wild type enzyme form. Inhibition of the enzyme leads to decreased levels of 2-hydroxyglutarate (2-HG) and promotion of proper differentiation and clonal proliferation of cells of the myeloid lineage. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The peak plasma concentration (C max ) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after a single dose of 100 mg, and 13.1 mcg/mL (CV% 45%) at steady state for 100 mg daily. The area under concentration-time curve (AUC) of enasidenib increases in an approximately dose-proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. The absolute bioavailability after a 100 mg oral dose of enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (T max ) is 4 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Human plasma protein binding of enasidenib and its metabolite AGI-16903 are 98.5% and 96.6% respectively in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism of enasidenib is mediated by multiple cytochrome P450 (CYP) enzymes (e.g.,CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UDP glucuronosyl transferases (UGTs) (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) in vitro. Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9) in vitro. Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Enasidenib has a terminal half-life of 7.9 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Enasidenib has a mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on animal embryo-fetal toxicity studies, enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on enasidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady-state clinical exposure based on the AUC at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with enasidenib. Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90 days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Idhifa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enasidenib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enasidenib is an isocitrate dehydrogenase-2 inhibitor used to treat relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Enasidenib interact? Information: •Drug A: Abatacept •Drug B: Enasidenib •Severity: MAJOR •Description: The metabolism of Enasidenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts, and increased percentages of mature myeloid cells. In a study involving adult patients with relapsed or refractory AML, an overall response rate of 40.3% was achieved in enasidenib therapy, which was associated with cellular differentiation and maturation without evidence of aplasia. The potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. No large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Enasidenib is a selective inhibitor of IDH2, a mitochondria-localized enzyme involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. Wild-type IDH proteins play a cruicial role in the Krebs/citric acid cycle where it catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. In comparison, mutant forms of IDH2 enzyme mediates a neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked cellular differentiation of hematopoietic progenitor cells. Enasidenib primarily targets the mutant IDH2 variants R140Q, R172S, and R172K with higher potency than the wild type enzyme form. Inhibition of the enzyme leads to decreased levels of 2-hydroxyglutarate (2-HG) and promotion of proper differentiation and clonal proliferation of cells of the myeloid lineage. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The peak plasma concentration (C max ) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after a single dose of 100 mg, and 13.1 mcg/mL (CV% 45%) at steady state for 100 mg daily. The area under concentration-time curve (AUC) of enasidenib increases in an approximately dose-proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. The absolute bioavailability after a 100 mg oral dose of enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (T max ) is 4 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Human plasma protein binding of enasidenib and its metabolite AGI-16903 are 98.5% and 96.6% respectively in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism of enasidenib is mediated by multiple cytochrome P450 (CYP) enzymes (e.g.,CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UDP glucuronosyl transferases (UGTs) (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) in vitro. Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9) in vitro. Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Enasidenib has a terminal half-life of 7.9 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Enasidenib has a mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on animal embryo-fetal toxicity studies, enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on enasidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady-state clinical exposure based on the AUC at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with enasidenib. Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90 days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Idhifa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enasidenib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enasidenib is an isocitrate dehydrogenase-2 inhibitor used to treat relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Encorafenib interact?

•Drug A: Abatacept •Drug B: Encorafenib •Severity: MODERATE •Description: The metabolism of Encorafenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Encorafenib is indicated in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Encorafenib has a pharmacologic profile that is distinct from that of other clinically active BRAF inhibitors and has shown improved efficacy in the treatment of metastatic melanoma. Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma. Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, the co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the co-administration compared to either drug alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. The co-administration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose-proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose-proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. After oral administration, the median T max of encorafenib is 2 hours. At least 86% of the dose is absorbed. Following administration of a single dose of encorafenib 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (C max ) decreased by 36% and there was no effect on AUC. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Encorafenib is 86% bound to human plasma proteins in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean (CV%) terminal half-life (t 1/2 ) of encorafenib is 3.5 hours (17%). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. In COLUMBUS, a phase 3 safety and efficacy trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use. Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication. Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib. Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Braftovi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Encorafenib interact? Information: •Drug A: Abatacept •Drug B: Encorafenib •Severity: MODERATE •Description: The metabolism of Encorafenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Encorafenib is indicated in combination with binimetinib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Encorafenib has a pharmacologic profile that is distinct from that of other clinically active BRAF inhibitors and has shown improved efficacy in the treatment of metastatic melanoma. Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma. Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, the co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the co-administration compared to either drug alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. The co-administration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36, and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 µM). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose-proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose-proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. After oral administration, the median T max of encorafenib is 2 hours. At least 86% of the dose is absorbed. Following administration of a single dose of encorafenib 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (C max ) decreased by 36% and there was no effect on AUC. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Encorafenib is 86% bound to human plasma proteins in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean (CV%) terminal half-life (t 1/2 ) of encorafenib is 3.5 hours (17%). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. In COLUMBUS, a phase 3 safety and efficacy trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use. Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication. Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib. Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Braftovi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Enflurane interact?

•Drug A: Abatacept •Drug B: Enflurane •Severity: MODERATE •Description: The metabolism of Enflurane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enflurane may be used for both the induction and maintenance of general anesthesia. It can also be used to induce analgesia for vaginal delivery. Low concentrations of enflurane can also be used as an adjunct to general anesthetic drugs during delivery by Cesarean section. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Enflurane rapidly induces anesthesia via the stimulation of inhibitory neural channels and the inhibition of excitatory neural channels. Muscle relaxation, obtundation of pharyngeal and laryngeal reflexes, and lowering of blood pressure are some of the main pharmacodynamic effects of this drug. Enflurane also decreases cardiac muscle contractility. High concentrations of enflurane may lead to uterine relaxation and increase the risk of uterine bleeding during delivery. Rare but clinically significant elevations in ALT may indicate hepatoxicity from the use of enflurane. In some susceptible patients, enflurane may cause malignant hyperthermia. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of enflurane is not completely established. Studies on rats indicate that enflurane binds to GABAA and glycine receptors, causing depressant effects at the ventral neural horn. It has been reported that 30% of the central nervous system depressant effects on the spinal cord after enflurane is administered are caused by the (GABA-A) receptor while binding to glycine receptors is responsible for about 20 % of the depressant effects. The relevance of these findings to humans is unknown. Other studies have found that enflurane binds to the calcium channels in the cardiac sarcoplasmic reticulum causing cardio depressant effects. Other studies support that this drug potentiates glycine receptors, which results in central nervous system depressant effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Enflurane is rapidly absorbed into the circulation through the lungs. The minimum alveolar concentration is oxygen is 1.68%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Enflurane distributes to the brain, blood, and subcutaneous fat. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding for enflurane is 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Enflurane is metabolized by the CYP2E1 enzyme in the liver to produce inorganic fluoride ions, the major metabolite of enflurane metabolism. One reference indicates that enflurane is only 2-5% eliminated after oxidative metabolism in the liver, however more recent evidence suggests that about 9% is eliminated via hepatic oxidation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Metabolism accounts for 5-9% of enflurane elimination, sometimes causing nephrotoxicity. Excretion through the skin is believed to be minimal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The LD50 of enflurane in rats is 14000 ppm/3 hour(s) when inhaled. There is limited information in the literature about enflurane overdose. Hepatotoxicity, cardiotoxicity, nephrotoxicity, and neurotoxicity are expected. One report in the literature of an enflurane overdose describes an accidental fatal overdose in a 21-year-old male. About 72 hours after death, high amounts of enflurane were found in the brain, blood, and subcutaneous fat. Gas chromatographic studies revealed enflurane concentrations of 350 mg/l-1 in the brain, 130 mg/l-1 in the blood, and 100 mg/l-1 in the subcutaneous fat. In the event of an enflurane overdose, immediately stop the administration of enflurane, establish a patent airway, and administer pure oxygen by assisted or controlled ventilation. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alyrane Efrane Enflurane Enflurano Enfluranum Methylflurether •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enflurane is a halogenated inhalational anesthetic agent used for the induction and maintenance of anesthesia and for analgesia during labor and delivery.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Enflurane interact? Information: •Drug A: Abatacept •Drug B: Enflurane •Severity: MODERATE •Description: The metabolism of Enflurane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enflurane may be used for both the induction and maintenance of general anesthesia. It can also be used to induce analgesia for vaginal delivery. Low concentrations of enflurane can also be used as an adjunct to general anesthetic drugs during delivery by Cesarean section. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Enflurane rapidly induces anesthesia via the stimulation of inhibitory neural channels and the inhibition of excitatory neural channels. Muscle relaxation, obtundation of pharyngeal and laryngeal reflexes, and lowering of blood pressure are some of the main pharmacodynamic effects of this drug. Enflurane also decreases cardiac muscle contractility. High concentrations of enflurane may lead to uterine relaxation and increase the risk of uterine bleeding during delivery. Rare but clinically significant elevations in ALT may indicate hepatoxicity from the use of enflurane. In some susceptible patients, enflurane may cause malignant hyperthermia. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of enflurane is not completely established. Studies on rats indicate that enflurane binds to GABAA and glycine receptors, causing depressant effects at the ventral neural horn. It has been reported that 30% of the central nervous system depressant effects on the spinal cord after enflurane is administered are caused by the (GABA-A) receptor while binding to glycine receptors is responsible for about 20 % of the depressant effects. The relevance of these findings to humans is unknown. Other studies have found that enflurane binds to the calcium channels in the cardiac sarcoplasmic reticulum causing cardio depressant effects. Other studies support that this drug potentiates glycine receptors, which results in central nervous system depressant effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Enflurane is rapidly absorbed into the circulation through the lungs. The minimum alveolar concentration is oxygen is 1.68%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Enflurane distributes to the brain, blood, and subcutaneous fat. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding for enflurane is 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Enflurane is metabolized by the CYP2E1 enzyme in the liver to produce inorganic fluoride ions, the major metabolite of enflurane metabolism. One reference indicates that enflurane is only 2-5% eliminated after oxidative metabolism in the liver, however more recent evidence suggests that about 9% is eliminated via hepatic oxidation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Metabolism accounts for 5-9% of enflurane elimination, sometimes causing nephrotoxicity. Excretion through the skin is believed to be minimal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The LD50 of enflurane in rats is 14000 ppm/3 hour(s) when inhaled. There is limited information in the literature about enflurane overdose. Hepatotoxicity, cardiotoxicity, nephrotoxicity, and neurotoxicity are expected. One report in the literature of an enflurane overdose describes an accidental fatal overdose in a 21-year-old male. About 72 hours after death, high amounts of enflurane were found in the brain, blood, and subcutaneous fat. Gas chromatographic studies revealed enflurane concentrations of 350 mg/l-1 in the brain, 130 mg/l-1 in the blood, and 100 mg/l-1 in the subcutaneous fat. In the event of an enflurane overdose, immediately stop the administration of enflurane, establish a patent airway, and administer pure oxygen by assisted or controlled ventilation. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alyrane Efrane Enflurane Enflurano Enfluranum Methylflurether •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enflurane is a halogenated inhalational anesthetic agent used for the induction and maintenance of anesthesia and for analgesia during labor and delivery. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Does Abatacept and Entecavir interact?

•Drug A: Abatacept •Drug B: Entecavir •Severity: MODERATE •Description: The metabolism of Entecavir can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). It is designed to selectively inhibit the Hepatitis B virus, blocking all three steps in the replication process. Entecavir is more efficient than an older Hepatitis B drug, lamivudine. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. In healthy subjects, the bioavailability of the tablet is 100% relative to the oral solution. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding of entecavir to human serum proteins in vitro is approximately 13%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. Entecavir is efficiently phosphorylated to the active triphosphate form. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The phosphorylated metabolite has a half-life of 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): renal cl=383.2 +/- 101.8 mL/min [Unimpaired renal function] renal cl=197.9 +/- 78.1 mL/min [Mild impaired renal function] renal cl=135.6 +/- 31.6 mL/min [Moderate impaired renal function] renal cl=40.3 +/- 10.1 mL/min [severe impaired renal function] apparent oral cl=588.1 +/- 153.7 mL/min [Unimpaired renal function] apparent oral cl=309.2 +/- 62.6 mL/min [Mild impaired renal function] apparent oral cl=226.3 +/- 60.1 mL/min [Moderate impaired renal function] apparent oral cl=100.6 +/- 29.1 mL/min [severe impaired renal function] apparent oral cl=50.6 +/- 16.5 mL/min [severe impaired renal function amnaged with Hemodialysis] apparent oral cl=35.7 +/- 19.6 mL/min [severe impaired renal function amnaged with CAPD] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Baraclude •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Entecavir Entecavirum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Entecavir is a nucleoside analogue used in the treatment of chronic hepatitis B for patients with active viral replication, histological evidence of active disease, or persistent elevations in liver transaminases.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Entecavir interact? Information: •Drug A: Abatacept •Drug B: Entecavir •Severity: MODERATE •Description: The metabolism of Entecavir can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). It is designed to selectively inhibit the Hepatitis B virus, blocking all three steps in the replication process. Entecavir is more efficient than an older Hepatitis B drug, lamivudine. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By competing with the natural substrate deoxyguanosine triphosphate, entecavir functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Upon activation by kinases, the drug can be incorporated into the DNA which has the ultimate effect of inhibiting the HBV polymerase activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. In healthy subjects, the bioavailability of the tablet is 100% relative to the oral solution. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding of entecavir to human serum proteins in vitro is approximately 13%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. Entecavir is efficiently phosphorylated to the active triphosphate form. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The phosphorylated metabolite has a half-life of 15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): renal cl=383.2 +/- 101.8 mL/min [Unimpaired renal function] renal cl=197.9 +/- 78.1 mL/min [Mild impaired renal function] renal cl=135.6 +/- 31.6 mL/min [Moderate impaired renal function] renal cl=40.3 +/- 10.1 mL/min [severe impaired renal function] apparent oral cl=588.1 +/- 153.7 mL/min [Unimpaired renal function] apparent oral cl=309.2 +/- 62.6 mL/min [Mild impaired renal function] apparent oral cl=226.3 +/- 60.1 mL/min [Moderate impaired renal function] apparent oral cl=100.6 +/- 29.1 mL/min [severe impaired renal function] apparent oral cl=50.6 +/- 16.5 mL/min [severe impaired renal function amnaged with Hemodialysis] apparent oral cl=35.7 +/- 19.6 mL/min [severe impaired renal function amnaged with CAPD] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Baraclude •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Entecavir Entecavirum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Entecavir is a nucleoside analogue used in the treatment of chronic hepatitis B for patients with active viral replication, histological evidence of active disease, or persistent elevations in liver transaminases. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Entrectinib interact?

•Drug A: Abatacept •Drug B: Entrectinib •Severity: MAJOR •Description: The metabolism of Entrectinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available. FoundationOne®Liquid CDx is the only FDA-approved test for the detection of ROS1 rearrangement(s) in NSCLC for selecting patients for treatment with entrectinib. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Entrectinib is over 99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rozlytrek •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Entrectinib interact? Information: •Drug A: Abatacept •Drug B: Entrectinib •Severity: MAJOR •Description: The metabolism of Entrectinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available. FoundationOne®Liquid CDx is the only FDA-approved test for the detection of ROS1 rearrangement(s) in NSCLC for selecting patients for treatment with entrectinib. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Entrectinib is over 99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rozlytrek •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Enzalutamide interact?

•Drug A: Abatacept •Drug B: Enzalutamide •Severity: MODERATE •Description: The metabolism of Enzalutamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enzalutamide is indicated for the treatment of castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer (mCSPC), and non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). It is also used in combination with talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Enzalutamide is a second-generation antiandrogen that blocks the activity of androgen and androgen receptor (AR) in prostate cancer. AR activity and prostate cancer progression are closely related due to the normal physiology of prostate cells, providing the rationale for androgen deprivation therapy (ADT). However, resistance will eventually arise after the commencement of ADT in 2-3 years due to the accumulation of mutations, including constitutively active mutation, AR overexpression, and changes in AR splicing variants. Enzalutamide was therefore designed to exploit these mutations. In vitro experiments in human prostate cancer cell line VCaP showed that enzalutamide can suppress cell growth and induce apoptosis while other antiandrogens like bicalutamide did not. Clinical trials on prostate cancer patients indicated that enzalutamide can lead to a decrease in serum PSA for at least 12 weeks, although this response can be short-lived and thus resulting in enzalutamide resistance. Patients receiving enzalutamide also had a 37% decreased in the risk of death compared to placebo. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Enzalutamide is a competitive androgen receptor (AR) inhibitor that has a threefold inhibition on the androgen signaling pathway without significant AR agonist activity. It inhibits androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with chromosomal DNA to upregulate oncogenes. Enzalutamide binds to the AR with 5 to 8-fold greater affinity than first-generation antiandrogens such as bicalutamide and only 2-3 fold reduced affinity than the natural ligand dihydrotestosterone. Molecular docking showed that enzalutamide binds to the ligand binding domain of the AR distinctive from that of bicalutamide. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The median Tmax is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (Cmax) for enzalutamide and N-desmethyl enzalutamide is 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (Cmin) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (%CV) volume of distribution after a single oral dose is 110 L (29%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of the dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean apparent clearance (CL/F) of enzalutamide after a single dose is 0.56 L/h (0.33 to 1.02 L/h). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10, and 30 mg/kg/day) resulted in systemic exposures (AUC) of approximately 0.04, 0.4, and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration. Based on animal studies, XTANDI may impair fertility in males of reproductive potential. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI. The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xtandi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enzalutamide is a second-generation androgen receptor inhibitor used to treat castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Enzalutamide interact? Information: •Drug A: Abatacept •Drug B: Enzalutamide •Severity: MODERATE •Description: The metabolism of Enzalutamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Enzalutamide is indicated for the treatment of castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer (mCSPC), and non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). It is also used in combination with talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Enzalutamide is a second-generation antiandrogen that blocks the activity of androgen and androgen receptor (AR) in prostate cancer. AR activity and prostate cancer progression are closely related due to the normal physiology of prostate cells, providing the rationale for androgen deprivation therapy (ADT). However, resistance will eventually arise after the commencement of ADT in 2-3 years due to the accumulation of mutations, including constitutively active mutation, AR overexpression, and changes in AR splicing variants. Enzalutamide was therefore designed to exploit these mutations. In vitro experiments in human prostate cancer cell line VCaP showed that enzalutamide can suppress cell growth and induce apoptosis while other antiandrogens like bicalutamide did not. Clinical trials on prostate cancer patients indicated that enzalutamide can lead to a decrease in serum PSA for at least 12 weeks, although this response can be short-lived and thus resulting in enzalutamide resistance. Patients receiving enzalutamide also had a 37% decreased in the risk of death compared to placebo. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Enzalutamide is a competitive androgen receptor (AR) inhibitor that has a threefold inhibition on the androgen signaling pathway without significant AR agonist activity. It inhibits androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with chromosomal DNA to upregulate oncogenes. Enzalutamide binds to the AR with 5 to 8-fold greater affinity than first-generation antiandrogens such as bicalutamide and only 2-3 fold reduced affinity than the natural ligand dihydrotestosterone. Molecular docking showed that enzalutamide binds to the ligand binding domain of the AR distinctive from that of bicalutamide. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The median Tmax is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (Cmax) for enzalutamide and N-desmethyl enzalutamide is 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (Cmin) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (%CV) volume of distribution after a single oral dose is 110 L (29%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of the dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean apparent clearance (CL/F) of enzalutamide after a single dose is 0.56 L/h (0.33 to 1.02 L/h). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10, and 30 mg/kg/day) resulted in systemic exposures (AUC) of approximately 0.04, 0.4, and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration. Based on animal studies, XTANDI may impair fertility in males of reproductive potential. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI. The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xtandi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Enzalutamide is a second-generation androgen receptor inhibitor used to treat castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Epinastine interact?

•Drug A: Abatacept •Drug B: Epinastine •Severity: MODERATE •Description: The metabolism of Epinastine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the prevention of itching associated with allergic conjunctivitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Epinastine is an antihistamine and an inhibitor of histamine release from the mast cell for topical administration to the eyes. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Epinastine is a topically active, direct H 1 -receptor antagonist and an inhibitor of the release of histamine from the mast cell. Epinastine is selective for the histamine H 1 -receptor and has affinity for the histamine H2 receptor. Epinastine also possesses affinity for the a1-, a2-, and 5-HT 2 -receptors. Epinastine does not penetrate the blood/brain barrier and, therefore, is not expected to induce side effects of the central nervous system. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Epinastine has a multiaction effect that inhibits the allergic response in 3 ways: 1. stabilizes mast cells by preventing mast cell degranulation to control the allergic response, 2. prevents histamine binding to both the H1- and H 2 -receptors to stop itching and provide lasting protection, and 3. prevents the release of proinflammatory chemical mediators from the blood vessel to halt progression of the allergic response. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of epinastine is about 40%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 64% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mainly excreted unchanged, less than 10% metabolized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Epinastine is mainly excreted unchanged. The renal elimination is mainly via active tubular secretion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 12 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 56 L/hr [patients with allergic conjunctivitis receiving one drop of ELESTAT® ophthalmic solution in each eye twice daily for seven days] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Elestat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epinastin Epinastina Epinastine épinastine Epinastinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Epinastine is an H1 receptor antagonist used to prevent itching in allergic conjunctivitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Epinastine interact? Information: •Drug A: Abatacept •Drug B: Epinastine •Severity: MODERATE •Description: The metabolism of Epinastine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the prevention of itching associated with allergic conjunctivitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Epinastine is an antihistamine and an inhibitor of histamine release from the mast cell for topical administration to the eyes. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Epinastine is a topically active, direct H 1 -receptor antagonist and an inhibitor of the release of histamine from the mast cell. Epinastine is selective for the histamine H 1 -receptor and has affinity for the histamine H2 receptor. Epinastine also possesses affinity for the a1-, a2-, and 5-HT 2 -receptors. Epinastine does not penetrate the blood/brain barrier and, therefore, is not expected to induce side effects of the central nervous system. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Epinastine has a multiaction effect that inhibits the allergic response in 3 ways: 1. stabilizes mast cells by preventing mast cell degranulation to control the allergic response, 2. prevents histamine binding to both the H1- and H 2 -receptors to stop itching and provide lasting protection, and 3. prevents the release of proinflammatory chemical mediators from the blood vessel to halt progression of the allergic response. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of epinastine is about 40%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 64% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mainly excreted unchanged, less than 10% metabolized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Epinastine is mainly excreted unchanged. The renal elimination is mainly via active tubular secretion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 12 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 56 L/hr [patients with allergic conjunctivitis receiving one drop of ELESTAT® ophthalmic solution in each eye twice daily for seven days] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Elestat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epinastin Epinastina Epinastine épinastine Epinastinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Epinastine is an H1 receptor antagonist used to prevent itching in allergic conjunctivitis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Epirubicin interact?

•Drug A: Abatacept •Drug B: Epirubicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Epirubicin is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Epirubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Epirubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Epirubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 100% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 21 ± 2 L/kg [60 mg/m2 Dose] 27 ± 11 L/kg [75 mg/m2 Dose] 23 ± 7 L/kg [120 mg/m2 Dose] 21 ± 7 L/kg [150 mg/m2 Dose] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively and rapidly metabolized in the liver. Epirubicin is also metabolized by other organs and cells, including red blood cells. The four main metabolic routes are: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol exhibits in vitro cytoxic activity (~10% that of epirubicin), but it is unlikely to reach sufficient concentrations in vivo to produce cytotoxic effects. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours and 33 hours, respectively •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 65 +/- 8 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 mg/m2] 83 +/- 14 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 75 mg/m2] 65 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 120 mg/m2] 69 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 150 mg/m2] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ellence, Pharmorubicin PFS •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Epirubicin is an anthracycline topoisomerase II inhibitor used as an adjuvant to treating axillary node metastases in patients who have undergone surgical resection of primary breast cancer.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Epirubicin interact? Information: •Drug A: Abatacept •Drug B: Epirubicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Epirubicin is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Epirubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Epirubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Epirubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 100% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 21 ± 2 L/kg [60 mg/m2 Dose] 27 ± 11 L/kg [75 mg/m2 Dose] 23 ± 7 L/kg [120 mg/m2 Dose] 21 ± 7 L/kg [150 mg/m2 Dose] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively and rapidly metabolized in the liver. Epirubicin is also metabolized by other organs and cells, including red blood cells. The four main metabolic routes are: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol exhibits in vitro cytoxic activity (~10% that of epirubicin), but it is unlikely to reach sufficient concentrations in vivo to produce cytotoxic effects. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours and 33 hours, respectively •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 65 +/- 8 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 mg/m2] 83 +/- 14 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 75 mg/m2] 65 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 120 mg/m2] 69 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 150 mg/m2] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ellence, Pharmorubicin PFS •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Epirubicin is an anthracycline topoisomerase II inhibitor used as an adjuvant to treating axillary node metastases in patients who have undergone surgical resection of primary breast cancer. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Eplerenone interact?

•Drug A: Abatacept •Drug B: Eplerenone •Severity: MODERATE •Description: The metabolism of Eplerenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of eplerenone is unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 43 to 90 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 50% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 4-6 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent plasma cl=10 L/hr •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inspra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eplerenone is an aldosterone receptor antagonist used to improve survival of patients with symptomatic heart failure and to reduce blood pressure.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Eplerenone interact? Information: •Drug A: Abatacept •Drug B: Eplerenone •Severity: MODERATE •Description: The metabolism of Eplerenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of eplerenone is unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 43 to 90 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 50% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 4-6 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent plasma cl=10 L/hr •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inspra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eplerenone is an aldosterone receptor antagonist used to improve survival of patients with symptomatic heart failure and to reduce blood pressure. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Erdafitinib interact?

•Drug A: Abatacept •Drug B: Erdafitinib •Severity: MAJOR •Description: The metabolism of Erdafitinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or FGFR2 genetic alterations and has progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The selection of patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib should be based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic like the FDA-approved therascreen FGFR RGQ RT-PCR Kit as developed by QIAGEN. This above indication is approved under accelerated approval by the FDA based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upon administration, it was observed that erdafitinib increased serum phosphate levels as a consequence of FGFR inhibition. Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5– 7.0 mg/dL in early cycles with continuous daily dosing. Subsequently, in erdafitinib clinical trials, the use of drugs that could increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives existed. To manage phosphate elevation, phosphate binders were utilized. Additionally, the concomitant use of agents that can alter serum phosphate levels before the initial erdafitinib dose increase period based on serum phosphate levels was also avoided. Furthermore, based on the evaluation of QTc interval in an open-label, dose escalation, and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fibroblast growth factor receptor (FGFR) is a transmembrane protein that is expressed ubiquitously in normal tissues and is involved in various endogenous bio-physiological processes including the homeostasis of phosphate and vitamin D, cell proliferation, cell anti-apoptotic signaling, and cell migration in a variety of cell types. Concurrently, genetic mutations such as gene amplification, point mutations, and chromosomal translocations of all four FGFR genes (FGFR1, FGFR2, FGFR3, and FGFR4) or deregulation of FGFR pathways have been implicated in the pathogenesis of various cancers, including urothelial cancer, as they promote cell proliferation, migration, angiogenesis, and anti-apoptosis. Erdafitinib is an oral selective pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of expressed FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data. In particular, erdafitinib demonstrates inhibition of FGFR phosphorylation and signaling as well as decreased cell viability in cell lines expressing FGFR genetic alterations. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation [CV%]) steady-state maximum observed plasma concentration (C max ), area under the curve (AUC tau ), and minimum observed plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeated once-daily dosing, erdafitinib exposure (maximum observed plasma concentration [C max ] and area under the plasma concentration-time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady-state was achieved after 2 weeks with once-daily dosing and the mean accumulation ratio was 4-fold. The median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). No clinically meaningful differences with erdafitinib pharmacokinetics were observed following the administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of the total caloric content of the meal from fat) in healthy subjects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution determined for erdafitinib is about 26 to 29 L in patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for erdafitinib is approximately 99.8%, and it was determined to be primarily bound to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes in humans to form the O-demethylated major metabolite.. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - no circulating metabolites were observed. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After administering a single oral dose of radiolabeled erdafitinib, about 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean effective half-life documented for erdafitinib is 59 hours, although it has also been observed between 50 to 60 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total apparent clearance (CL/F) documented for erdafitinib is about 0.362 L/h, while the oral clearance has been observed to be approximately 0.26 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo- fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib. Erdafitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential. Safety and effectiveness of erdafitinib in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between these patients and younger patients in the use of erdafitinib. Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9 3/ 3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9 3/ 3 genotype. Carcinogenicity studies have not been conducted with erdafitinib. Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Balversa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erdafitinib is a fibroblast growth factor receptor tyrosine kinase inhibitor used to treat locally advanced or metastatic urothelial carcinoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Erdafitinib interact? Information: •Drug A: Abatacept •Drug B: Erdafitinib •Severity: MAJOR •Description: The metabolism of Erdafitinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or FGFR2 genetic alterations and has progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The selection of patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib should be based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic like the FDA-approved therascreen FGFR RGQ RT-PCR Kit as developed by QIAGEN. This above indication is approved under accelerated approval by the FDA based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upon administration, it was observed that erdafitinib increased serum phosphate levels as a consequence of FGFR inhibition. Erdafitinib should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5– 7.0 mg/dL in early cycles with continuous daily dosing. Subsequently, in erdafitinib clinical trials, the use of drugs that could increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives existed. To manage phosphate elevation, phosphate binders were utilized. Additionally, the concomitant use of agents that can alter serum phosphate levels before the initial erdafitinib dose increase period based on serum phosphate levels was also avoided. Furthermore, based on the evaluation of QTc interval in an open-label, dose escalation, and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fibroblast growth factor receptor (FGFR) is a transmembrane protein that is expressed ubiquitously in normal tissues and is involved in various endogenous bio-physiological processes including the homeostasis of phosphate and vitamin D, cell proliferation, cell anti-apoptotic signaling, and cell migration in a variety of cell types. Concurrently, genetic mutations such as gene amplification, point mutations, and chromosomal translocations of all four FGFR genes (FGFR1, FGFR2, FGFR3, and FGFR4) or deregulation of FGFR pathways have been implicated in the pathogenesis of various cancers, including urothelial cancer, as they promote cell proliferation, migration, angiogenesis, and anti-apoptosis. Erdafitinib is an oral selective pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of expressed FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data. In particular, erdafitinib demonstrates inhibition of FGFR phosphorylation and signaling as well as decreased cell viability in cell lines expressing FGFR genetic alterations. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation [CV%]) steady-state maximum observed plasma concentration (C max ), area under the curve (AUC tau ), and minimum observed plasma concentration (C min ) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively. Following single and repeated once-daily dosing, erdafitinib exposure (maximum observed plasma concentration [C max ] and area under the plasma concentration-time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady-state was achieved after 2 weeks with once-daily dosing and the mean accumulation ratio was 4-fold. The median time to achieve peak plasma concentration (t max ) was 2.5 hours (range: 2 to 6 hours). No clinically meaningful differences with erdafitinib pharmacokinetics were observed following the administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of the total caloric content of the meal from fat) in healthy subjects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution determined for erdafitinib is about 26 to 29 L in patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for erdafitinib is approximately 99.8%, and it was determined to be primarily bound to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes in humans to form the O-demethylated major metabolite.. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - no circulating metabolites were observed. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After administering a single oral dose of radiolabeled erdafitinib, about 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean effective half-life documented for erdafitinib is 59 hours, although it has also been observed between 50 to 60 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total apparent clearance (CL/F) documented for erdafitinib is about 0.362 L/h, while the oral clearance has been observed to be approximately 0.26 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on the mechanism of action and findings in animal reproduction studies, erdafitinib can cause fetal harm when administered to a pregnant woman. There are no available data on erdafitinib use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo- fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with erdafitinib and for one month following the last dose. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with erdafitinib. Erdafitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with erdafitinib and for one month after the last dose. Based on findings from animal studies, erdafitinib may impair fertility in females of reproductive potential. Safety and effectiveness of erdafitinib in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between these patients and younger patients in the use of erdafitinib. Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9 3/ 3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9 3/ 3 genotype. Carcinogenicity studies have not been conducted with erdafitinib. Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with erdafitinib. In the 3-month repeat-dose toxicity study, erdafitinib showed effects on female reproductive organs (necrosis of the ovarian corpora lutea) in rats at an exposure less than the human exposure (AUC) at maximum recommended human dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Balversa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erdafitinib is a fibroblast growth factor receptor tyrosine kinase inhibitor used to treat locally advanced or metastatic urothelial carcinoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Ergotamine interact?

•Drug A: Abatacept •Drug B: Ergotamine •Severity: MAJOR •Description: The metabolism of Ergotamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants, or so called "histaminic cephalalgia". •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist. The pharmacological properties of ergotamine are extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon their site, and it is a highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The pain of a migraine attack is believed to be due to greatly increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extracranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyperperfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ergotamine acts on migraine by one of two proposed mechanisms: 1) activation of 5-HT 1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache, and 2) activation of 5-HT 1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The bioavailability of sublingually administered ergotamine has not been determined. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Ergotamine is metabolized by the liver by largely undefined pathways, and 90% of the metabolites are excreted in the bile. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Signs of overexposure include irritation, nausea, vomiting, headache, diarrhea, thirst, coldness of skin, pruritus, weak pulse, numbness, tingling of extremities, and confusion. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ergomar, Migergot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ergotamin Ergotamina Ergotamine Ergotaminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ergotamine is an alpha-1 selective adrenergic agonist vasoconstrictor used to treat migraines with or without aura and cluster headaches.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Ergotamine interact? Information: •Drug A: Abatacept •Drug B: Ergotamine •Severity: MAJOR •Description: The metabolism of Ergotamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants, or so called "histaminic cephalalgia". •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist. The pharmacological properties of ergotamine are extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon their site, and it is a highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The pain of a migraine attack is believed to be due to greatly increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extracranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyperperfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ergotamine acts on migraine by one of two proposed mechanisms: 1) activation of 5-HT 1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache, and 2) activation of 5-HT 1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The bioavailability of sublingually administered ergotamine has not been determined. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Ergotamine is metabolized by the liver by largely undefined pathways, and 90% of the metabolites are excreted in the bile. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Signs of overexposure include irritation, nausea, vomiting, headache, diarrhea, thirst, coldness of skin, pruritus, weak pulse, numbness, tingling of extremities, and confusion. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ergomar, Migergot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ergotamin Ergotamina Ergotamine Ergotaminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ergotamine is an alpha-1 selective adrenergic agonist vasoconstrictor used to treat migraines with or without aura and cluster headaches. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Eribulin interact?

•Drug A: Abatacept •Drug B: Eribulin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Eribulin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Linear •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. [FDA] •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 43 L/m2 to 114 L/m2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 49 to 65%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There are no major human metabolites of eribulin, CYP3A4 negligibly metabolizes eribulin in vitro. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eribulin is eliminated primarily in feces unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): about 40 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 1.16 L/hr/m2 to 2.42 L/hr/m2 (dose range of 0.25 mg/m2 to 4.0 mg/m2). [FDA] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin (5 percent). [Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.] Single doses of 0.75 mg/kg were lethal to rats and two doses of 0.075 mg/kg were lethal to dogs. The no-observed-adverse-effect level (NOAEL) in rats and dogs were 0.015 and 0.0045 mg/kg/day, respectively. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Halaven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eribulin is a microtubule inhibitor used to treat metastatic breast cancer and metastatic or unresectable liposarcoma.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Eribulin interact? Information: •Drug A: Abatacept •Drug B: Eribulin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Eribulin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Linear •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. [FDA] •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 43 L/m2 to 114 L/m2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 49 to 65%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There are no major human metabolites of eribulin, CYP3A4 negligibly metabolizes eribulin in vitro. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Eribulin is eliminated primarily in feces unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): about 40 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 1.16 L/hr/m2 to 2.42 L/hr/m2 (dose range of 0.25 mg/m2 to 4.0 mg/m2). [FDA] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin (5 percent). [Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.] Single doses of 0.75 mg/kg were lethal to rats and two doses of 0.075 mg/kg were lethal to dogs. The no-observed-adverse-effect level (NOAEL) in rats and dogs were 0.015 and 0.0045 mg/kg/day, respectively. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Halaven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eribulin is a microtubule inhibitor used to treat metastatic breast cancer and metastatic or unresectable liposarcoma. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Erlotinib interact?

•Drug A: Abatacept •Drug B: Erlotinib •Severity: MAJOR •Description: The metabolism of Erlotinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erlotinib is indicated for: The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent volume of distribution = 232 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG) •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Median half-life of 36.2 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Smokers have a 24% higher rate of erlotinib clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tarceva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Erlotinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erlotinib is an EGFR tyrosine kinase inhibitor used to treat certain small cell lung cancers or advanced metastatic pancreatic cancers.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Erlotinib interact? Information: •Drug A: Abatacept •Drug B: Erlotinib •Severity: MAJOR •Description: The metabolism of Erlotinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erlotinib is indicated for: The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent volume of distribution = 232 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG) •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Median half-life of 36.2 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Smokers have a 24% higher rate of erlotinib clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tarceva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Erlotinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erlotinib is an EGFR tyrosine kinase inhibitor used to treat certain small cell lung cancers or advanced metastatic pancreatic cancers. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Erythromycin interact?

•Drug A: Abatacept •Drug B: Erythromycin •Severity: MODERATE •Description: The metabolism of Erythromycin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erythromycin is indicated in the treatment of infections caused by susceptible strains of various bacteria. The indications for erythromycin have been summarized by body system below: Respiratory infections Mild to moderate upper respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with appropriate doses of sulfonamides) can be treated with erythromycin. Mild to moderate lower-respiratory tract infections due to susceptible strains of Streptococcus pneumoniae or Streptococcus pyogenes may also be treated. Erythromycin treats listeriosis caused by Listeria monocytogenes may also be treated with erythromycin. Erythromycin is indicated to treat pertussis (whooping cough) caused by Bordetella pertussis. It is effective in eliminating the causative organism from the nasopharynx of infected individuals, rendering them noninfectious. Clinical studies suggest that erythromycin may aid in the prevention of pertussis infection for individuals who have been exposed to the bacteria. Respiratory tract infections due to Mycoplasma pneumoniae may also be treated with erythromycin. Despite the fact that no controlled clinical efficacy studies have been conducted to this date, in vitro and certain preliminary clinical study results indicate that erythromycin may be an effective treatment in Legionnaires’ Disease. Finally, erythromycin is indicated to treat diphtheria and other infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent carrier status and to eradicate the organism in existing carriers. In addition to the prevention of diphtheria, erythromycin can be used to prevent rheumatic fever in penicillin intolerant patients. Skin infections Mild to moderate skin or skin structure infections caused by Streptococcus pyogenes or Staphylococcus aureus may be treated with erythromycin, however, resistant staphylococcal organisms may emerge. Erythromycin can also be used to treat erythrasma, an infectious condition caused by Corynebacterium minutissimum. Gastrointestinal infections Intestinal amebiasis caused by Entamoeba histolytica can be treated with oral erythromycin. Extraenteric amebiasis warrants treatment with other antimicrobial drugs. Genital infections/STIs Erythromycin can be used as an alternative drug in treating acute pelvic inflammatory disease caused by N. gonorrheae in female patients who have demonstrated hypersensitivity or intolerance to penicillin. Syphilis, caused by Treponema pallidum, can be treated with erythromycin. It serves as an alternative treatment for primary syphilis in patients who have demonstrated penicillin hypersensitivity. Erythromycin can also be used in the primary stage of primary syphilis. Another approved indication of erythromycin is to treat chlamydial infections that cause conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections occurring in pregnancy. It is indicated as an alternative option to tetracyclines for the treatment of uncomplicated rectal, urethral and endocervical infections in adults caused by Chlamydia trachomatis. Erythromycin can be used in nongonococcal urethritis can be used when tetracyclines cannot be administered. Finally, erythromycin is indicated to treat nongonococcal urethritis due to Ureaplasma urealyticum. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Macrolides, such as erythromycin, stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Erythromycin does not exert effects on nucleic acid synthesis. This drug has been shown to be active against most strains of the following microorganisms, effectively treating both in vitro and clinical infections. Despite this, it is important to perform bacterial susceptibility testing before administering this antibiotic, as resistance is a common issue that may affect treatment. A note on antimicrobial resistance, pseudomembranous colitis, and hepatotoxicity Many strains of Haemophilus influenzae are resistant to erythromycin alone but are found to be susceptible to erythromycin and sulfonamides used in combination. It is important to note that Staphylococci that are resistant to erythromycin may emerge during erythromycin and/or sulfonamide therapy. Pseudomembranous colitis has been reported with most antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, the physician should consider this diagnosis in patients with diarrhea after the administration of antibacterial agents. Erythromycin can cause hepatic dysfunction, cholestatic jaundice, and abnormal liver transaminases, particularly when erythromycin estolate is administered. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Erythromycin acts by inhibition of protein synthesis by binding to the 23S ribosomal RNA molecule in the 50S subunit of ribosomes in susceptible bacterial organisms. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. This results in the control of various bacterial infections. The strong affinity of macrolides, including erythromycin, for bacterial ribosomes, supports their broad‐spectrum antibacterial activities. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally administered erythromycin is readily absorbed. Food intake does not appear to exert effects on serum concentrations of erythromycin. Some interindividual variation exists in terms of erythromycin absorption, which may impact absorption to varying degrees. The Cmax of erythromycin is 1.8 mcg/L and the Tmax is 1.2 hours. The serum AUC of erythromycin after the administration of a 500mg oral dose was 7.3±3.9 mg.h/l in one pharmacokinetic study. Erythromycin is well known for a bioavailability that is variable (18-45%) after oral administration and its susceptibility to broken down under acidic conditions. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Erythromycin is found in most body fluids and accumulates in leucocytes and inflammatory liquid. Spinal fluid concentrations of erythromycin are low, however, the diffusion of erythromycin through the blood-brain barrier increases in meningitis, likely due to the presence of inflamed tissues which are easily penetrated. Erythromycin crosses the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Erythromycin demonstrates 93% serum protein binding in the erythromycin propionate form. Another resource indicates that erythromycin protein binding ranges from 80 to 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic first-pass metabolism contributes significantly to erythromycin metabolism after an oral dose. Erythromycin is partially metabolized by CYP3A4 enzyme to N-desmethylerythromycin. Erythromycin is also hydrolyzed to anhydro forms (anhydroerythromycin [AHE] and other metabolites), and this process is promoted by acidic conditions. AHE is inactive against microbes but inhibits hepatic drug oxidation and is therefore considered to be an important contributor to erythromycin drug-drug interactions. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In patients with normal liver function, erythromycin concentrates in the liver and is then excreted in the bile. Under 5% of the orally administered dose of erythromycin is found excreted in the urine. A high percentage of absorbed erythromycin is not accounted for, but is likely metabolized. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of oral erythromycin was 3.5 hours according to one study and ranged between 2.4-3.1 hours in another study. Repetitive dosing of erythromycin leads to increased elimination half-life. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of erythromycin in healthy subjects was 0.53 ± 0.13 l/h/kg after a 125mg intravenous dose. In a clinical study of healthy patients and patients with liver cirrhosis, clearance of erythromycin was significantly reduced in those with severe liver cirrhosis. The clearance in cirrhotic patients was 42.2 ± 10.1 l h–1 versus 113.2 ± 44.2 l h-1 in healthy patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 The oral LD50 of erythromycin in rats is 9272 mg/kg. Overdose information Symptoms of overdose may include diarrhea, nausea, stomach cramps, and vomiting. Erythromycin should immediately be discontinued in cases of overdose. Rapid elimination of unabsorbed drug should be attempted. Supportive measures should be initiated. Erythromycin is not adequately removed by peritoneal dialysis or hemodialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aktipak, Apo-Erythro-S, Benzamycin, E.E.S., Ery, Ery-tab, Erygel, Eryped, Erythro, Erythrocin, Erythrocin Stearate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abomacetin Eritromicina Erythromycin Erythromycin A Erythromycin C érythromycine Erythromycinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erythromycin is a macrolide antibiotic used to treat and prevent a variety of bacterial infections.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Erythromycin interact? Information: •Drug A: Abatacept •Drug B: Erythromycin •Severity: MODERATE •Description: The metabolism of Erythromycin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Erythromycin is indicated in the treatment of infections caused by susceptible strains of various bacteria. The indications for erythromycin have been summarized by body system below: Respiratory infections Mild to moderate upper respiratory tract infections caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with appropriate doses of sulfonamides) can be treated with erythromycin. Mild to moderate lower-respiratory tract infections due to susceptible strains of Streptococcus pneumoniae or Streptococcus pyogenes may also be treated. Erythromycin treats listeriosis caused by Listeria monocytogenes may also be treated with erythromycin. Erythromycin is indicated to treat pertussis (whooping cough) caused by Bordetella pertussis. It is effective in eliminating the causative organism from the nasopharynx of infected individuals, rendering them noninfectious. Clinical studies suggest that erythromycin may aid in the prevention of pertussis infection for individuals who have been exposed to the bacteria. Respiratory tract infections due to Mycoplasma pneumoniae may also be treated with erythromycin. Despite the fact that no controlled clinical efficacy studies have been conducted to this date, in vitro and certain preliminary clinical study results indicate that erythromycin may be an effective treatment in Legionnaires’ Disease. Finally, erythromycin is indicated to treat diphtheria and other infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent carrier status and to eradicate the organism in existing carriers. In addition to the prevention of diphtheria, erythromycin can be used to prevent rheumatic fever in penicillin intolerant patients. Skin infections Mild to moderate skin or skin structure infections caused by Streptococcus pyogenes or Staphylococcus aureus may be treated with erythromycin, however, resistant staphylococcal organisms may emerge. Erythromycin can also be used to treat erythrasma, an infectious condition caused by Corynebacterium minutissimum. Gastrointestinal infections Intestinal amebiasis caused by Entamoeba histolytica can be treated with oral erythromycin. Extraenteric amebiasis warrants treatment with other antimicrobial drugs. Genital infections/STIs Erythromycin can be used as an alternative drug in treating acute pelvic inflammatory disease caused by N. gonorrheae in female patients who have demonstrated hypersensitivity or intolerance to penicillin. Syphilis, caused by Treponema pallidum, can be treated with erythromycin. It serves as an alternative treatment for primary syphilis in patients who have demonstrated penicillin hypersensitivity. Erythromycin can also be used in the primary stage of primary syphilis. Another approved indication of erythromycin is to treat chlamydial infections that cause conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections occurring in pregnancy. It is indicated as an alternative option to tetracyclines for the treatment of uncomplicated rectal, urethral and endocervical infections in adults caused by Chlamydia trachomatis. Erythromycin can be used in nongonococcal urethritis can be used when tetracyclines cannot be administered. Finally, erythromycin is indicated to treat nongonococcal urethritis due to Ureaplasma urealyticum. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Macrolides, such as erythromycin, stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Erythromycin does not exert effects on nucleic acid synthesis. This drug has been shown to be active against most strains of the following microorganisms, effectively treating both in vitro and clinical infections. Despite this, it is important to perform bacterial susceptibility testing before administering this antibiotic, as resistance is a common issue that may affect treatment. A note on antimicrobial resistance, pseudomembranous colitis, and hepatotoxicity Many strains of Haemophilus influenzae are resistant to erythromycin alone but are found to be susceptible to erythromycin and sulfonamides used in combination. It is important to note that Staphylococci that are resistant to erythromycin may emerge during erythromycin and/or sulfonamide therapy. Pseudomembranous colitis has been reported with most antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, the physician should consider this diagnosis in patients with diarrhea after the administration of antibacterial agents. Erythromycin can cause hepatic dysfunction, cholestatic jaundice, and abnormal liver transaminases, particularly when erythromycin estolate is administered. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Erythromycin acts by inhibition of protein synthesis by binding to the 23S ribosomal RNA molecule in the 50S subunit of ribosomes in susceptible bacterial organisms. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. This results in the control of various bacterial infections. The strong affinity of macrolides, including erythromycin, for bacterial ribosomes, supports their broad‐spectrum antibacterial activities. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally administered erythromycin is readily absorbed. Food intake does not appear to exert effects on serum concentrations of erythromycin. Some interindividual variation exists in terms of erythromycin absorption, which may impact absorption to varying degrees. The Cmax of erythromycin is 1.8 mcg/L and the Tmax is 1.2 hours. The serum AUC of erythromycin after the administration of a 500mg oral dose was 7.3±3.9 mg.h/l in one pharmacokinetic study. Erythromycin is well known for a bioavailability that is variable (18-45%) after oral administration and its susceptibility to broken down under acidic conditions. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Erythromycin is found in most body fluids and accumulates in leucocytes and inflammatory liquid. Spinal fluid concentrations of erythromycin are low, however, the diffusion of erythromycin through the blood-brain barrier increases in meningitis, likely due to the presence of inflamed tissues which are easily penetrated. Erythromycin crosses the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Erythromycin demonstrates 93% serum protein binding in the erythromycin propionate form. Another resource indicates that erythromycin protein binding ranges from 80 to 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic first-pass metabolism contributes significantly to erythromycin metabolism after an oral dose. Erythromycin is partially metabolized by CYP3A4 enzyme to N-desmethylerythromycin. Erythromycin is also hydrolyzed to anhydro forms (anhydroerythromycin [AHE] and other metabolites), and this process is promoted by acidic conditions. AHE is inactive against microbes but inhibits hepatic drug oxidation and is therefore considered to be an important contributor to erythromycin drug-drug interactions. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In patients with normal liver function, erythromycin concentrates in the liver and is then excreted in the bile. Under 5% of the orally administered dose of erythromycin is found excreted in the urine. A high percentage of absorbed erythromycin is not accounted for, but is likely metabolized. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of oral erythromycin was 3.5 hours according to one study and ranged between 2.4-3.1 hours in another study. Repetitive dosing of erythromycin leads to increased elimination half-life. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of erythromycin in healthy subjects was 0.53 ± 0.13 l/h/kg after a 125mg intravenous dose. In a clinical study of healthy patients and patients with liver cirrhosis, clearance of erythromycin was significantly reduced in those with severe liver cirrhosis. The clearance in cirrhotic patients was 42.2 ± 10.1 l h–1 versus 113.2 ± 44.2 l h-1 in healthy patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 The oral LD50 of erythromycin in rats is 9272 mg/kg. Overdose information Symptoms of overdose may include diarrhea, nausea, stomach cramps, and vomiting. Erythromycin should immediately be discontinued in cases of overdose. Rapid elimination of unabsorbed drug should be attempted. Supportive measures should be initiated. Erythromycin is not adequately removed by peritoneal dialysis or hemodialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aktipak, Apo-Erythro-S, Benzamycin, E.E.S., Ery, Ery-tab, Erygel, Eryped, Erythro, Erythrocin, Erythrocin Stearate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Abomacetin Eritromicina Erythromycin Erythromycin A Erythromycin C érythromycine Erythromycinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Erythromycin is a macrolide antibiotic used to treat and prevent a variety of bacterial infections. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Escitalopram interact?

•Drug A: Abatacept •Drug B: Escitalopram •Severity: MODERATE •Description: The metabolism of Escitalopram can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Escitalopram is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years old and older and for the acute treatment of generalized anxiety disorder (GAD) in adults and pediatric patients 7 years old and older. It is additionally indicated for symptomatic relief of obsessive-compulsive disorder (OCD) in Canada. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Escitalopram belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT 1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T max occurs after about 4-5 hours. C max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C max and 24h AUC, comparatively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Escitalopram exhibits relatively low protein binding at approximately 55-56%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose may include CNS effects (dizziness, convulsions, coma, somnolence), gastrointestinal distress (nausea, vomiting), and/or cardiac abnormalities (hypotension, tachycardia, ECG changes). There is no specific antidote for escitalopram overdose. Management of overdose should focus on monitoring for cardiac abnormalities and changes to vital signs as well as treatment with supportive measures as indicated. As escitalopram is highly distributed into tissue following oral administration, forced diuresis, dialysis, and other methods of extracting drug from plasma are unlikely to be beneficial. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cipralex, Lexapro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Citalopram Escitalopram Escitalopramum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Escitalopram is a selective serotonin re-uptake inhibitor used in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and other select psychiatric disorders such as obsessive-compulsive disorder (OCD).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Escitalopram interact? Information: •Drug A: Abatacept •Drug B: Escitalopram •Severity: MODERATE •Description: The metabolism of Escitalopram can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Escitalopram is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years old and older and for the acute treatment of generalized anxiety disorder (GAD) in adults and pediatric patients 7 years old and older. It is additionally indicated for symptomatic relief of obsessive-compulsive disorder (OCD) in Canada. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Escitalopram belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with paroxetine, is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT 1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T max occurs after about 4-5 hours. C max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C max and 24h AUC, comparatively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Escitalopram exhibits relatively low protein binding at approximately 55-56%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose may include CNS effects (dizziness, convulsions, coma, somnolence), gastrointestinal distress (nausea, vomiting), and/or cardiac abnormalities (hypotension, tachycardia, ECG changes). There is no specific antidote for escitalopram overdose. Management of overdose should focus on monitoring for cardiac abnormalities and changes to vital signs as well as treatment with supportive measures as indicated. As escitalopram is highly distributed into tissue following oral administration, forced diuresis, dialysis, and other methods of extracting drug from plasma are unlikely to be beneficial. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cipralex, Lexapro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Citalopram Escitalopram Escitalopramum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Escitalopram is a selective serotonin re-uptake inhibitor used in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and other select psychiatric disorders such as obsessive-compulsive disorder (OCD). Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Esketamine interact?

•Drug A: Abatacept •Drug B: Esketamine •Severity: MODERATE •Description: The metabolism of Esketamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Esketamine is indicated in combination with an oral antidepressant for the treatment of treatment-resistant depression in adults. It is also indicated for the treatment of depressive symptoms in adults with major depressive disorder experiencing acute suicidal ideation or behaviour. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): General effects Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion. Effects on cardiac electrophysiology The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine. Effects on blood pressure Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours. Cognitive effects In a study of healthy volunteers, one dose of this agent caused decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration. Reports of long-term memory or cognitive impairment have been made following repeated ketamine misuse or abuse. No adverse effects of esketamine nasal spray on cognitive function were seen in a one-year open-label safety study. The long-term cognitive effects of esketamine have not been studied for more than a 1 year period, therefore, the risk of cognitive decline with long-term use is not yet confirmed. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine ( noresketamine ) shows activity at the same receptor with a weaker affinity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of esketamine is about 43% to 45%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esketamine is mainly metabolized to the noresketamine metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life (t1/2) ranges from 7 to 12 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance of esketamine is approximately 89 L/hour following intravenous administration. Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Ketamine hydrochloride LD50: 447 mg/kg, Rat (oral) Neurotoxicity In a one-dose neuronal toxicity study with esketamine intranasal administration to adult female rats, no finding of neuronal vacuolation in the brain occurred with doses up to the equivalent of the maximum recommended human dose of 84 mg/day. In a second single dose neurotoxicity study performed with intranasal esketamine administration in adult female rats, no observation of neuronal necrosis up to a dose equivalent to the maximum recommended human dose was made. Neuronal vacuolation was not evaluated in this study. The relevance of these findings in humans is unknown at this time. A note on dependence and tolerance Reports of physical dependence have been made following prolonged use of ketamine. Withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug is a common manifestation of drug dependence. There were no withdrawal symptoms observed up to 4 weeks in subjects after stopping esketamine treatment. Withdrawal symptoms have been observed after the discontinuation of frequently used (more than weekly) high doses of ketamine for a longer duration. These symptoms of withdrawal have a higher chance of occurring if esketamine was similarly abused. Symptoms of withdrawal reported to be associated with daily intake of high ketamine doses include craving, fatigue, poor appetite, and anxiety. Therefore, monitor esketamine-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug. Tolerance has been reported with prolonged use of ketamine. Tolerance is characterized by a decreased response to a drug following repeated doses (i.e., a higher dose of a drug is required to produce the same effect that was previously achieved at a lower dose). Comparable tolerance would be expected to occur with long-term use of esketamine. Use in pregnancy This drug may cause fetal harm, based on the findings of animal studies. Pregnancy planning and prevention in females of reproductive potential should occur before the initiation of esketamine treatment. There is a pregnancy registry for women who exposed to esketamine during pregnancy. The goal of the registry is to gather data about the health of women and infants exposed to esketamine. Use in lactation Esketamine is present in human milk. No safety data on the effects of esketamine on the breastfed infant or on milk production are available. Studies in young animals report neurotoxicity. Due to the risk of neurotoxicity, advise patients that breastfeeding is not recommended during treatment with this drug. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Spravato •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-ketamine Esketamine L-ketamine S-ketamine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esketamine is a NMDA receptor antagonist used for treatment-resistant depression.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Esketamine interact? Information: •Drug A: Abatacept •Drug B: Esketamine •Severity: MODERATE •Description: The metabolism of Esketamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Esketamine is indicated in combination with an oral antidepressant for the treatment of treatment-resistant depression in adults. It is also indicated for the treatment of depressive symptoms in adults with major depressive disorder experiencing acute suicidal ideation or behaviour. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): General effects Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion. Effects on cardiac electrophysiology The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine. Effects on blood pressure Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours. Cognitive effects In a study of healthy volunteers, one dose of this agent caused decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration. Reports of long-term memory or cognitive impairment have been made following repeated ketamine misuse or abuse. No adverse effects of esketamine nasal spray on cognitive function were seen in a one-year open-label safety study. The long-term cognitive effects of esketamine have not been studied for more than a 1 year period, therefore, the risk of cognitive decline with long-term use is not yet confirmed. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine ( noresketamine ) shows activity at the same receptor with a weaker affinity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of esketamine is about 43% to 45%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esketamine is mainly metabolized to the noresketamine metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life (t1/2) ranges from 7 to 12 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance of esketamine is approximately 89 L/hour following intravenous administration. Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Ketamine hydrochloride LD50: 447 mg/kg, Rat (oral) Neurotoxicity In a one-dose neuronal toxicity study with esketamine intranasal administration to adult female rats, no finding of neuronal vacuolation in the brain occurred with doses up to the equivalent of the maximum recommended human dose of 84 mg/day. In a second single dose neurotoxicity study performed with intranasal esketamine administration in adult female rats, no observation of neuronal necrosis up to a dose equivalent to the maximum recommended human dose was made. Neuronal vacuolation was not evaluated in this study. The relevance of these findings in humans is unknown at this time. A note on dependence and tolerance Reports of physical dependence have been made following prolonged use of ketamine. Withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug is a common manifestation of drug dependence. There were no withdrawal symptoms observed up to 4 weeks in subjects after stopping esketamine treatment. Withdrawal symptoms have been observed after the discontinuation of frequently used (more than weekly) high doses of ketamine for a longer duration. These symptoms of withdrawal have a higher chance of occurring if esketamine was similarly abused. Symptoms of withdrawal reported to be associated with daily intake of high ketamine doses include craving, fatigue, poor appetite, and anxiety. Therefore, monitor esketamine-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug. Tolerance has been reported with prolonged use of ketamine. Tolerance is characterized by a decreased response to a drug following repeated doses (i.e., a higher dose of a drug is required to produce the same effect that was previously achieved at a lower dose). Comparable tolerance would be expected to occur with long-term use of esketamine. Use in pregnancy This drug may cause fetal harm, based on the findings of animal studies. Pregnancy planning and prevention in females of reproductive potential should occur before the initiation of esketamine treatment. There is a pregnancy registry for women who exposed to esketamine during pregnancy. The goal of the registry is to gather data about the health of women and infants exposed to esketamine. Use in lactation Esketamine is present in human milk. No safety data on the effects of esketamine on the breastfed infant or on milk production are available. Studies in young animals report neurotoxicity. Due to the risk of neurotoxicity, advise patients that breastfeeding is not recommended during treatment with this drug. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Spravato •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-ketamine Esketamine L-ketamine S-ketamine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esketamine is a NMDA receptor antagonist used for treatment-resistant depression. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Esmolol interact?

•Drug A: Abatacept •Drug B: Esmolol •Severity: MODERATE •Description: The metabolism of Esmolol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Esmolol interact? Information: •Drug A: Abatacept •Drug B: Esmolol •Severity: MODERATE •Description: The metabolism of Esmolol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Esomeprazole interact?

•Drug A: Abatacept •Drug B: Esomeprazole •Severity: MODERATE •Description: The metabolism of Esomeprazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Esomeprazole is indicated for the treatment of acid-reflux disorders including healing and maintenance of erosive esophagitis, and symptomatic gastroesophageal reflux disease (GERD), peptic ulcer disease, H. pylori eradication, prevention of gastrointestinal bleeds with NSAID use, and for the long-term treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Esomeprazole is a compound that inhibits gastric acid secretion and is indicated in the treatment of gastroesophageal reflux disease (GERD), the healing of erosive esophagitis, and H. pylori eradication to reduce the risk of duodenal ulcer recurrence. Esomeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H /K ATPase at the secretory surface of the gastric parietal cell. By doing so, it inhibits acid secretion into the gsatric lumen. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Esomeprazole is the s-isomer of Omeprazole, which is a racemate of the S- and R-enantiomer. Esomeprazole has been shown to inhibit acid secretion to a similar extent as Omeprazole, without any significant differences between the two compounds in vitro. PPIs such as esomeprazole have also been shown to inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme necessary for cardiovascular health. DDAH inhibition causes a consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginie (ADMA), which is thought to cause the association of PPIs with increased risk of cardiovascular events in patients with unstable coronary syndromes. Due to their good safety profile and as several PPIs are available over the counter without a prescription, their current use in North America is widespread. Long term use of PPIs such as esomeprazole has been associated with possible adverse effects, however, including increased susceptibility to bacterial infections (including gastrointestinal C. difficile ), reduced absorption of micronutrients including iron and B12, and an increased risk of developing hypomagnesemia and hypocalcemia which may contribute to osteoporosis and bone fractures later in life. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Esomeprazole exerts its stomach acid-suppressing effects by preventing the final step in gastric acid production by covalently binding to sulfhydryl groups of cysteines found on the (H+, K+)-ATPase enzyme at the secretory surface of gastric parietal cells. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. As the binding of esomeprazole to the (H+, K+)-ATPase enzyme is irreversible and new enzyme needs to be expressed in order to resume acid secretion, esomeprazole's duration of antisecretory effect that persists longer than 24 hours. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration, peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 μmol hr/L on Day 1 to 11.2 μmol hr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of Esomeprazole is decreased by 43% to 53% after food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before meals. Combination Therapy with Antimicrobials: Esomeprazole magnesium 40 mg once daily was given in combination with Clarithromycin 500 mg twice daily and Amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 µmol/L. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15 to 20% of Asians lack CYP2C19 and are termed Poor Metabolizers. However, the influence of CYP 2C19 polymorphism is less pronounced for esomeprazole than for omeprazole. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2. Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer. Nine major urinary metabolites have been detected. The two main metabolites have been identified as hydroxyesomeprazole and the corresponding carboxylic acid. Three major metabolites have been identified in plasma: the 5-O-desmethyl- and sulphone derivatives and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1-1.5 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Blurred vision, confusion, drowsiness, dry mouth, flushing headache, nausea, rapid heartbeat, sweating •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nexium, Vimovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-omeprazole Esomeprazol Ésoméprazole Esomeprazole Esomeprazolum Perprazole •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esomeprazole is a proton pump inhibitor used to treat GERD, reduce the risk of NSAID associated gastric ulcers, eradicate H. pylori, and to treat conditions causing gastric acid hypersecretion.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Esomeprazole interact? Information: •Drug A: Abatacept •Drug B: Esomeprazole •Severity: MODERATE •Description: The metabolism of Esomeprazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Esomeprazole is indicated for the treatment of acid-reflux disorders including healing and maintenance of erosive esophagitis, and symptomatic gastroesophageal reflux disease (GERD), peptic ulcer disease, H. pylori eradication, prevention of gastrointestinal bleeds with NSAID use, and for the long-term treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Esomeprazole is a compound that inhibits gastric acid secretion and is indicated in the treatment of gastroesophageal reflux disease (GERD), the healing of erosive esophagitis, and H. pylori eradication to reduce the risk of duodenal ulcer recurrence. Esomeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H /K ATPase at the secretory surface of the gastric parietal cell. By doing so, it inhibits acid secretion into the gsatric lumen. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Esomeprazole is the s-isomer of Omeprazole, which is a racemate of the S- and R-enantiomer. Esomeprazole has been shown to inhibit acid secretion to a similar extent as Omeprazole, without any significant differences between the two compounds in vitro. PPIs such as esomeprazole have also been shown to inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme necessary for cardiovascular health. DDAH inhibition causes a consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginie (ADMA), which is thought to cause the association of PPIs with increased risk of cardiovascular events in patients with unstable coronary syndromes. Due to their good safety profile and as several PPIs are available over the counter without a prescription, their current use in North America is widespread. Long term use of PPIs such as esomeprazole has been associated with possible adverse effects, however, including increased susceptibility to bacterial infections (including gastrointestinal C. difficile ), reduced absorption of micronutrients including iron and B12, and an increased risk of developing hypomagnesemia and hypocalcemia which may contribute to osteoporosis and bone fractures later in life. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Esomeprazole exerts its stomach acid-suppressing effects by preventing the final step in gastric acid production by covalently binding to sulfhydryl groups of cysteines found on the (H+, K+)-ATPase enzyme at the secretory surface of gastric parietal cells. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. As the binding of esomeprazole to the (H+, K+)-ATPase enzyme is irreversible and new enzyme needs to be expressed in order to resume acid secretion, esomeprazole's duration of antisecretory effect that persists longer than 24 hours. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration, peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 μmol hr/L on Day 1 to 11.2 μmol hr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of Esomeprazole is decreased by 43% to 53% after food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before meals. Combination Therapy with Antimicrobials: Esomeprazole magnesium 40 mg once daily was given in combination with Clarithromycin 500 mg twice daily and Amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 µmol/L. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15 to 20% of Asians lack CYP2C19 and are termed Poor Metabolizers. However, the influence of CYP 2C19 polymorphism is less pronounced for esomeprazole than for omeprazole. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2. Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer. Nine major urinary metabolites have been detected. The two main metabolites have been identified as hydroxyesomeprazole and the corresponding carboxylic acid. Three major metabolites have been identified in plasma: the 5-O-desmethyl- and sulphone derivatives and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1-1.5 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Blurred vision, confusion, drowsiness, dry mouth, flushing headache, nausea, rapid heartbeat, sweating •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nexium, Vimovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-omeprazole Esomeprazol Ésoméprazole Esomeprazole Esomeprazolum Perprazole •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Esomeprazole is a proton pump inhibitor used to treat GERD, reduce the risk of NSAID associated gastric ulcers, eradicate H. pylori, and to treat conditions causing gastric acid hypersecretion. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Estradiol acetate interact?

•Drug A: Abatacept •Drug B: Estradiol acetate •Severity: MODERATE •Description: The metabolism of Estradiol acetate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Femring is indicated for the treatment of vasomotor and urogenital symptoms associated with menopause. Use of Femring (estradiol acetate) has been shown to improve symptoms caused by atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Drug delivery from Femring is rapid for the first hour and then declines to a relatively constant rate for the remainder of the 3-month dosing interval. Estradiol acetate is rapidly hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (tmax) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). Following the maximum concentration (Cmax=1129pg/mL), serum estradiol decreases rapidly such that by 24 to 48 hours postdose, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely (>95%) bound to sex hormone binding globulin (SHBG) and to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Can cause nausea and vomiting, and withdrawal bleeding may occur in females. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Femring •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estradiol 3-acetate Estradiol acetate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol acetate is an estrogen used to treat vasomotor symptoms and moderate to severe vulvar and vaginal atrophy from menopause.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estradiol acetate interact? Information: •Drug A: Abatacept •Drug B: Estradiol acetate •Severity: MODERATE •Description: The metabolism of Estradiol acetate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Femring is indicated for the treatment of vasomotor and urogenital symptoms associated with menopause. Use of Femring (estradiol acetate) has been shown to improve symptoms caused by atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Drug delivery from Femring is rapid for the first hour and then declines to a relatively constant rate for the remainder of the 3-month dosing interval. Estradiol acetate is rapidly hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (tmax) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). Following the maximum concentration (Cmax=1129pg/mL), serum estradiol decreases rapidly such that by 24 to 48 hours postdose, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely (>95%) bound to sex hormone binding globulin (SHBG) and to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Can cause nausea and vomiting, and withdrawal bleeding may occur in females. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Femring •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estradiol 3-acetate Estradiol acetate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol acetate is an estrogen used to treat vasomotor symptoms and moderate to severe vulvar and vaginal atrophy from menopause. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Estradiol benzoate interact?

•Drug A: Abatacept •Drug B: Estradiol benzoate •Severity: MODERATE •Description: The metabolism of Estradiol benzoate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol benzoate is not currently available in any FDA or Health Canada approved products. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely (>95%) bound to sex hormone binding globulin (SHBG) and to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol benzoate is an estrogen indicated in combination with progesterone for the treatment of irregular menstruation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estradiol benzoate interact? Information: •Drug A: Abatacept •Drug B: Estradiol benzoate •Severity: MODERATE •Description: The metabolism of Estradiol benzoate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol benzoate is not currently available in any FDA or Health Canada approved products. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely (>95%) bound to sex hormone binding globulin (SHBG) and to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol benzoate is an estrogen indicated in combination with progesterone for the treatment of irregular menstruation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Estradiol cypionate interact?

•Drug A: Abatacept •Drug B: Estradiol cypionate •Severity: MODERATE •Description: The metabolism of Estradiol cypionate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Depo-Estradiol intramuscular depot injection is indicated for the treatment of moderate to severe vasomotor symptoms and hypoestrogenism due to hypogonadism. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause and of hypoestrogenism, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Depo-estradiol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol cypionate is an estradiol prodrug used to treat vasomotor symptoms and hypoestrogenisms from hypogonadism.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estradiol cypionate interact? Information: •Drug A: Abatacept •Drug B: Estradiol cypionate •Severity: MODERATE •Description: The metabolism of Estradiol cypionate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Depo-Estradiol intramuscular depot injection is indicated for the treatment of moderate to severe vasomotor symptoms and hypoestrogenism due to hypogonadism. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause and of hypoestrogenism, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Depo-estradiol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol cypionate is an estradiol prodrug used to treat vasomotor symptoms and hypoestrogenisms from hypogonadism. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Estradiol valerate interact?

•Drug A: Abatacept •Drug B: Estradiol valerate •Severity: MODERATE •Description: The metabolism of Estradiol valerate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Delestrogen, Natazia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estradiol valerate interact? Information: •Drug A: Abatacept •Drug B: Estradiol valerate •Severity: MODERATE •Description: The metabolism of Estradiol valerate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Delestrogen, Natazia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Estradiol interact?

•Drug A: Abatacept •Drug B: Estradiol •Severity: MODERATE •Description: The metabolism of Estradiol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol is indicated in various preparations for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of postmenopausal osteoporosis. It is also used for the treatment of breast cancer (only for palliation therapy) in certain men or women with metastatic disease, and for the treatment of androgen-dependent prostate cancer (only for palliation therapy). It is also used in combination with other hormones as a component of oral contraceptive pills for preventing pregnancy (most commonly as Ethinylestradiol, a synthetic form of estradiol). A note on duration of treatment Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as concerns were raised regarding estrogen use. Specifically, the combined estrogen–progestin group was discontinued after about 5 years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events. Following extensive critique of the WHI results, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years postmenopause) in low doses, and in women without a history of breast cancer or increased risk of cardiovascular or thromboembolic disease. Estrogen for postmenopausal symptoms should always be given with a progestin component due to estrogen's stimulatory effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer over the long-term. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. A note on hyper-coagulable state, cardiovascular health, and blood pressure Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption of several formulations of estradiol is described below: Oral tablets and injections First-pass metabolism in the gastrointestinal tract rapidly breaks down estradiol tablets before entering the systemic circulation. The bioavailability of oral estrogens is said to be 2-10% due to significant first-pass effects. The esterification of estradiol improves the administration (such as with estradiol valerate) or to sustain release from intramuscular depot injections (including estradiol cypionate ) via higher lipophilicity. After absorption, the esters are cleaved, which leads to the release of endogenous estradiol, or 17β-estradiol. Transdermal preparations The transdermal preparations slowly release estradiol through intact skin, which sustains circulating levels of estradiol during a 1 week period of time. Notably, the bioavailability of estradiol after transdermal administration is about 20 times higher than after oral administration. Transdermal estradiol avoids first pass metabolism effects that reduce bioavailability. Administration via the buttock leads to a Cmax of about 174 pg/mL compared to 147 pg/mL via the abdomen. Spray preparations After daily administration, the spray formulations of estradiol reach steady state within 7-8 days. After 3 sprays daily, Cmax is about 54 pg/mL with a Tmax of 20 hours. AUC is about 471 pg•hr/mL. Vaginal ring and cream preparations Estradiol is efficiently absorbed through the mucous membranes of the vagina. The vaginal administration of estrogens evades first-pass metabolism. Tmax after vaginal ring delivery ranges from 0.5 to 1 hour. Cmax is about 63 pg/mL. The vaginal cream preparation has a Cmax of estradiol (a component of Premarin vaginal estrogen conjugate cream) was a Cmax of 12.8 ± 16.6 pg/mL, Tmax of 8.5 ± 6.2 hours, with an AUC of 231 ± 285 pg•hr/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Estrogens administered exogenously distribute in a similar fashion to endogenous estrogens. They can be found throughout the body, especially in the sex hormone target organs, such as the breast, ovaries and uterus. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): More than 95% of estrogens are found to circulate in the blood bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenously administered estrogens are metabolized in the same fashion as endogenous estrogens. Metabolic transformation occurs primarily in the liver and intestine. Estradiol is metabolized to estrone, and both are converted to estriol, which is later excreted in the urine. Sulfate and glucuronide conjugation estrogens also take place in the liver. Biliary secretion of metabolic conjugates are released into the intestine, and estrogen hydrolysis in the gut occurs, followed by reabsorption. The CYP3A4 hepatic cytochrome enzyme is heavily involved in the metabolism of estradiol. CYP1A2 also plays a role. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol is excreted in the urine with both glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-lives for various estrogen products post oral or intravenous administration has been reported to range from 1-12 hours. One pharmacokinetic study of oral estradiol valerate administration in postmenopausal women revealed a terminal elimination half-life of 16.9 ± 6.0 h. A pharmacokinetic study of intravenous estradiol administration in postmenopausal women showed an elimination half-life of 27.45 ± 5.65 minutes. The half-life of estradiol appears to vary by route of administration. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In one pharmacokinetic study, the clearance of orally administered micronized estradiol in postmenopausal women was 29.9±15.5 mL/min/kg. Another study revealed a clearance of intravenously administered estradiol was 1.3 mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The NOAEL (no-observed-adverse-effect-level) oral toxicity of estradiol after 90 day in rats was 0.003 mg/kg/day for blood, female reproductive, and male reproductive, endocrine, and liver toxicity. Oral TDLO of ethinyl estradiol is 21 mg/kg/21D intermittent, woman) with an oral LD50 of 960 mg/kg in the rat. There is limited information in the literature regarding estrogen overdose. Estradiol overdose likely leads to the occurrence of estrogen-associated adverse effects, including nausea, vomiting, abdominal pain, breast tenderness, venous thrombosis, and vaginal bleeding. It is generally recommend to discontinue estradiol treatment and offer supportive care in the case of an overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Activella 1/0.5 28 Day, Activelle, Amabelz 0.5/0.1 28 Day, Angeliq 0.25/0.5 28 Day, Bijuva, Climara, Climara Pro, Combipatch, Divigel, Dotti, Elestrin, Estalis, Estrace, Estradot, Estring, Estrogel, Etyqa 0.5/0.1 28 Day, Evamist, Imvexxy 4 Mcg Starter Pack, Lopreeza 1/0.5 28 Day, Lyllana, Menostar, Mimvey, Minivelle, Myfembree, Oesclim, Oriahnn 28 Day Kit, Prefest 30 Day, Vagifem, Vivelle, Yuvafem •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17beta oestradiol beta-Estradiol cis-Estradiol Estradiol Estradiol-17beta Estradiolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol is an estrogenic steroid used to treat vasomotor symptoms of vulvar and vaginal atrophy in menopause, hypoestrogenism, prevention of postmenopausal osteoporosis, treatment of breast cancer, and advanced androgen-dependent carcinoma of the prostate.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estradiol interact? Information: •Drug A: Abatacept •Drug B: Estradiol •Severity: MODERATE •Description: The metabolism of Estradiol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estradiol is indicated in various preparations for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of postmenopausal osteoporosis. It is also used for the treatment of breast cancer (only for palliation therapy) in certain men or women with metastatic disease, and for the treatment of androgen-dependent prostate cancer (only for palliation therapy). It is also used in combination with other hormones as a component of oral contraceptive pills for preventing pregnancy (most commonly as Ethinylestradiol, a synthetic form of estradiol). A note on duration of treatment Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as concerns were raised regarding estrogen use. Specifically, the combined estrogen–progestin group was discontinued after about 5 years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events. Following extensive critique of the WHI results, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years postmenopause) in low doses, and in women without a history of breast cancer or increased risk of cardiovascular or thromboembolic disease. Estrogen for postmenopausal symptoms should always be given with a progestin component due to estrogen's stimulatory effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer over the long-term. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. A note on hyper-coagulable state, cardiovascular health, and blood pressure Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption of several formulations of estradiol is described below: Oral tablets and injections First-pass metabolism in the gastrointestinal tract rapidly breaks down estradiol tablets before entering the systemic circulation. The bioavailability of oral estrogens is said to be 2-10% due to significant first-pass effects. The esterification of estradiol improves the administration (such as with estradiol valerate) or to sustain release from intramuscular depot injections (including estradiol cypionate ) via higher lipophilicity. After absorption, the esters are cleaved, which leads to the release of endogenous estradiol, or 17β-estradiol. Transdermal preparations The transdermal preparations slowly release estradiol through intact skin, which sustains circulating levels of estradiol during a 1 week period of time. Notably, the bioavailability of estradiol after transdermal administration is about 20 times higher than after oral administration. Transdermal estradiol avoids first pass metabolism effects that reduce bioavailability. Administration via the buttock leads to a Cmax of about 174 pg/mL compared to 147 pg/mL via the abdomen. Spray preparations After daily administration, the spray formulations of estradiol reach steady state within 7-8 days. After 3 sprays daily, Cmax is about 54 pg/mL with a Tmax of 20 hours. AUC is about 471 pg•hr/mL. Vaginal ring and cream preparations Estradiol is efficiently absorbed through the mucous membranes of the vagina. The vaginal administration of estrogens evades first-pass metabolism. Tmax after vaginal ring delivery ranges from 0.5 to 1 hour. Cmax is about 63 pg/mL. The vaginal cream preparation has a Cmax of estradiol (a component of Premarin vaginal estrogen conjugate cream) was a Cmax of 12.8 ± 16.6 pg/mL, Tmax of 8.5 ± 6.2 hours, with an AUC of 231 ± 285 pg•hr/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Estrogens administered exogenously distribute in a similar fashion to endogenous estrogens. They can be found throughout the body, especially in the sex hormone target organs, such as the breast, ovaries and uterus. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): More than 95% of estrogens are found to circulate in the blood bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenously administered estrogens are metabolized in the same fashion as endogenous estrogens. Metabolic transformation occurs primarily in the liver and intestine. Estradiol is metabolized to estrone, and both are converted to estriol, which is later excreted in the urine. Sulfate and glucuronide conjugation estrogens also take place in the liver. Biliary secretion of metabolic conjugates are released into the intestine, and estrogen hydrolysis in the gut occurs, followed by reabsorption. The CYP3A4 hepatic cytochrome enzyme is heavily involved in the metabolism of estradiol. CYP1A2 also plays a role. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol is excreted in the urine with both glucuronide and sulfate conjugates. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-lives for various estrogen products post oral or intravenous administration has been reported to range from 1-12 hours. One pharmacokinetic study of oral estradiol valerate administration in postmenopausal women revealed a terminal elimination half-life of 16.9 ± 6.0 h. A pharmacokinetic study of intravenous estradiol administration in postmenopausal women showed an elimination half-life of 27.45 ± 5.65 minutes. The half-life of estradiol appears to vary by route of administration. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In one pharmacokinetic study, the clearance of orally administered micronized estradiol in postmenopausal women was 29.9±15.5 mL/min/kg. Another study revealed a clearance of intravenously administered estradiol was 1.3 mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The NOAEL (no-observed-adverse-effect-level) oral toxicity of estradiol after 90 day in rats was 0.003 mg/kg/day for blood, female reproductive, and male reproductive, endocrine, and liver toxicity. Oral TDLO of ethinyl estradiol is 21 mg/kg/21D intermittent, woman) with an oral LD50 of 960 mg/kg in the rat. There is limited information in the literature regarding estrogen overdose. Estradiol overdose likely leads to the occurrence of estrogen-associated adverse effects, including nausea, vomiting, abdominal pain, breast tenderness, venous thrombosis, and vaginal bleeding. It is generally recommend to discontinue estradiol treatment and offer supportive care in the case of an overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Activella 1/0.5 28 Day, Activelle, Amabelz 0.5/0.1 28 Day, Angeliq 0.25/0.5 28 Day, Bijuva, Climara, Climara Pro, Combipatch, Divigel, Dotti, Elestrin, Estalis, Estrace, Estradot, Estring, Estrogel, Etyqa 0.5/0.1 28 Day, Evamist, Imvexxy 4 Mcg Starter Pack, Lopreeza 1/0.5 28 Day, Lyllana, Menostar, Mimvey, Minivelle, Myfembree, Oesclim, Oriahnn 28 Day Kit, Prefest 30 Day, Vagifem, Vivelle, Yuvafem •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17beta oestradiol beta-Estradiol cis-Estradiol Estradiol Estradiol-17beta Estradiolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estradiol is an estrogenic steroid used to treat vasomotor symptoms of vulvar and vaginal atrophy in menopause, hypoestrogenism, prevention of postmenopausal osteoporosis, treatment of breast cancer, and advanced androgen-dependent carcinoma of the prostate. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Estramustine interact?

•Drug A: Abatacept •Drug B: Estramustine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Estramustine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components.. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estramustine is a derivative of estradiol with a nitrogen mustard moiety. This gives it alkylating properties. In vivo, the nitrogen mustard component is active and can alklyate DNA and other cellular components (such as tubulin components) of rapidly dividing cells. This causes DNA strandbreaks or misscoding events. This leads to apoptosis and cell death. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Emcyt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estramustina Estramustine Estramustinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estramustine is an antineoplastic agent used for the management of metastatic and/or progressive prostate cancer in palliative setting.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Estramustine interact? Information: •Drug A: Abatacept •Drug B: Estramustine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Estramustine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components.. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estramustine is a derivative of estradiol with a nitrogen mustard moiety. This gives it alkylating properties. In vivo, the nitrogen mustard component is active and can alklyate DNA and other cellular components (such as tubulin components) of rapidly dividing cells. This causes DNA strandbreaks or misscoding events. This leads to apoptosis and cell death. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Emcyt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estramustina Estramustine Estramustinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estramustine is an antineoplastic agent used for the management of metastatic and/or progressive prostate cancer in palliative setting. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Estrone sulfate interact?

•Drug A: Abatacept •Drug B: Estrone sulfate •Severity: MODERATE •Description: The metabolism of Estrone sulfate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estropipate is used for the treatment of moderate to severe vasomotor symptoms associated with the monopause, and moderate to severe symptoms of vulval and vaginal atrophy associated with the menopause. It is also used to treat hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and prevent postmenopausal osteoporosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estropipate is an estrogenic substance. It acts as naturally produced estrogen does. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Estropipate is well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estrone 3-sulfate Estrone bisulfate Estrone hemisulfate Estrone hydrogen sulfate Estrone sulphate Estrone, hydrogen sulfate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estrone sulfate is an estrogen used as monotherapy or in several combination hormone replacement products for managing menopause symptoms and hormone disorders.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Estrone sulfate interact? Information: •Drug A: Abatacept •Drug B: Estrone sulfate •Severity: MODERATE •Description: The metabolism of Estrone sulfate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Estropipate is used for the treatment of moderate to severe vasomotor symptoms associated with the monopause, and moderate to severe symptoms of vulval and vaginal atrophy associated with the menopause. It is also used to treat hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and prevent postmenopausal osteoporosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Estropipate is an estrogenic substance. It acts as naturally produced estrogen does. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Estropipate is well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estrone 3-sulfate Estrone bisulfate Estrone hemisulfate Estrone hydrogen sulfate Estrone sulphate Estrone, hydrogen sulfate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Estrone sulfate is an estrogen used as monotherapy or in several combination hormone replacement products for managing menopause symptoms and hormone disorders. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Eszopiclone interact?

•Drug A: Abatacept •Drug B: Eszopiclone •Severity: MODERATE •Description: The metabolism of Eszopiclone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eszopiclone is indicated for the treatment of insomnia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eszopiclone rapidly induces sleep and decreases sleep latency. It also aids in the maintenance of sleep, preventing frequent awakenings. This drug has shown anticonvulsant and muscle relaxant properties in animals but is used in humans for its sedating effects. Eszopiclone is a central nervous system depressant with various effects. These include changes in alertness and motor coordination and the risk of next morning impairment, increasing with the amount of eszopiclone administered. Exercise caution and advise against driving a motor vehicle or activities that require full mental alertness the next morning. Complex sleep behaviors may result from eszopiclone use. Eszopiclone should be discontinued in these cases. Avoid the use of alcohol and other CNS depressants when eszopiclone is administered. Advise patients to skip the eszopiclone dose if alcohol has been consumed before bed or during the evening. Use the smallest dose of eszopiclone as possible, especially in elderly patients, who may experience exaggerated drug effects. Though the potential for dependence and abuse with eszopiclone is lower than for other hypnotic drugs, this drug has been abused and is known to cause dependence. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of eszopiclone is unknown at this time but is thought to occur via binding with the GABA receptor complexes at binding sites located near benzodiazepine receptors, possibly explaining its hypnotic and sedative effects. It has particular affinity for GABA-A (or GABAA) receptor subunits 1, 3 and 5. Eszopiclone increases GABA-A channel currents significantly. GABA-A channels are major inhibitory channels that cause CNS depression when their receptors are activated. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eszopiclone is rapidly absorbed and the peak concentration is reached within about 1 hour after oral administration. The mean AUC after a 3 mg dose of eszopiclone was 278 ng/mL × h. The consumption of a high-fat has been shown to slow absorption. Steady-state concentrations of eszopiclone are reached within 24-48 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of eszopiclone is estimated at 89.9L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This drug is 52-59% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following oral administration, eszopiclone is extensively biotransformed and the major metabolites are S-desmethylzopiclone and zopiclone-N-oxide, which are largely inactive.. The enzymes involved in the metabolism of eszopiclone are CYP3A (the primary metabolizing enzyme), CYP2C8, and CYP2E1. The N-oxide derivative shows weak pharmacological activity in animals. The N-desmethyl metabolite is pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only about 10% of an eszopiclone dose is found excreted in the urine as the parent drug. As much as 75% of an orally administered dose of racemic zopiclone as is found to be excreted in the urine in the form of metabolites. Eszopiclone, the S-isomer of racemic zopiclone, would likely show the same excretion pattern. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life is 6.1 hours in healthy patients but is prolonged in various patients, including those with hepatic impairment, elderly patients, in addition to those taking CYP3A enzyme inhibiting drugs. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean clearance of eszopiclone in young, healthy volunteers was 184 mL/min in one pharmacokinetic study. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 of eszopiclone in rats is 980 mg/kg and 3200 mg/kg in rabbits. Symptoms of overdose may include mental status changes and somnolence, demonstrating general exaggeration of the drug's pharmacological effects. Perform gastric lavage and offer supportive treatment if an overdose is suspected, including intravenous fluids as required. Flumazenil may be used. Vital signs should be closely monitored in addition to patient symptoms. Appropriate medical interventions should be employed. The possibility of an overdose with multiple drugs should be considered. Ensure to contact the local poison control center for the most updated management of hypnotic drug overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lunesta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Zopiclone Esopiclone Eszopiclone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eszopiclone is a sedative-hypnotic used in the treatment of insomnia, improving both the latency phase and the maintenance phase of sleep.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Eszopiclone interact? Information: •Drug A: Abatacept •Drug B: Eszopiclone •Severity: MODERATE •Description: The metabolism of Eszopiclone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Eszopiclone is indicated for the treatment of insomnia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Eszopiclone rapidly induces sleep and decreases sleep latency. It also aids in the maintenance of sleep, preventing frequent awakenings. This drug has shown anticonvulsant and muscle relaxant properties in animals but is used in humans for its sedating effects. Eszopiclone is a central nervous system depressant with various effects. These include changes in alertness and motor coordination and the risk of next morning impairment, increasing with the amount of eszopiclone administered. Exercise caution and advise against driving a motor vehicle or activities that require full mental alertness the next morning. Complex sleep behaviors may result from eszopiclone use. Eszopiclone should be discontinued in these cases. Avoid the use of alcohol and other CNS depressants when eszopiclone is administered. Advise patients to skip the eszopiclone dose if alcohol has been consumed before bed or during the evening. Use the smallest dose of eszopiclone as possible, especially in elderly patients, who may experience exaggerated drug effects. Though the potential for dependence and abuse with eszopiclone is lower than for other hypnotic drugs, this drug has been abused and is known to cause dependence. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of eszopiclone is unknown at this time but is thought to occur via binding with the GABA receptor complexes at binding sites located near benzodiazepine receptors, possibly explaining its hypnotic and sedative effects. It has particular affinity for GABA-A (or GABAA) receptor subunits 1, 3 and 5. Eszopiclone increases GABA-A channel currents significantly. GABA-A channels are major inhibitory channels that cause CNS depression when their receptors are activated. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Eszopiclone is rapidly absorbed and the peak concentration is reached within about 1 hour after oral administration. The mean AUC after a 3 mg dose of eszopiclone was 278 ng/mL × h. The consumption of a high-fat has been shown to slow absorption. Steady-state concentrations of eszopiclone are reached within 24-48 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of eszopiclone is estimated at 89.9L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This drug is 52-59% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following oral administration, eszopiclone is extensively biotransformed and the major metabolites are S-desmethylzopiclone and zopiclone-N-oxide, which are largely inactive.. The enzymes involved in the metabolism of eszopiclone are CYP3A (the primary metabolizing enzyme), CYP2C8, and CYP2E1. The N-oxide derivative shows weak pharmacological activity in animals. The N-desmethyl metabolite is pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only about 10% of an eszopiclone dose is found excreted in the urine as the parent drug. As much as 75% of an orally administered dose of racemic zopiclone as is found to be excreted in the urine in the form of metabolites. Eszopiclone, the S-isomer of racemic zopiclone, would likely show the same excretion pattern. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life is 6.1 hours in healthy patients but is prolonged in various patients, including those with hepatic impairment, elderly patients, in addition to those taking CYP3A enzyme inhibiting drugs. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean clearance of eszopiclone in young, healthy volunteers was 184 mL/min in one pharmacokinetic study. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 of eszopiclone in rats is 980 mg/kg and 3200 mg/kg in rabbits. Symptoms of overdose may include mental status changes and somnolence, demonstrating general exaggeration of the drug's pharmacological effects. Perform gastric lavage and offer supportive treatment if an overdose is suspected, including intravenous fluids as required. Flumazenil may be used. Vital signs should be closely monitored in addition to patient symptoms. Appropriate medical interventions should be employed. The possibility of an overdose with multiple drugs should be considered. Ensure to contact the local poison control center for the most updated management of hypnotic drug overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lunesta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-Zopiclone Esopiclone Eszopiclone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Eszopiclone is a sedative-hypnotic used in the treatment of insomnia, improving both the latency phase and the maintenance phase of sleep. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Does Abatacept and Etanercept interact?

•Drug A: Abatacept •Drug B: Etanercept •Severity: MAJOR •Description: The risk or severity of infection can be increased when Etanercept is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etanercept is indicated for the treatment of moderately to severely active rheumatoid arthritis in adults and in chronic moderate to severe plaque psoriasis in patients 4 years of age and older. It is also used to manage signs and symptoms of polyarticular idiopathic arthritis and Juvenile Psoriatic Arthritis in those aged 2 years and older. Etanercept is also used to manage the symptoms of psoriatic arthritis and ankylosing spondylitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etanercept binds specifically to tumor necrosis factor (TNF) and thereby modulates biological processes that are induced or regulated by TNF. Such processes or molecules affected include the level of adhesion molecules expressed, as well as serum levels of cytokines and matrix metalloproteinases. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There are two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75). The biological activity of TNF is dependent upon binding to either cell surface receptor (p75 or p55). Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules, thereby effectively removing them from circulation. Notably, etancerpt is only capable of binding to the active trimeric form of TNF as its binding site is located in the cleft between subunits. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Increased levels of TNF are found in tissues and fluids of those with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Population pharmacokinetic modeling in adults with RA, AS, or who were healthy showed a subcutaneous bioavailability of 56.9% with a Ka of 0.0223/h. Another model in pediatric JIA patients showed an increased Ka of 0.05/h with a high mean interindividual variability of 215%. Cmax after a single 25 mg subcutaneous dose of Enbrel is reported as 1.1 mcg/L with a Tmax of 69 h. Cmax after repeated dosing is reported as 2.4 mcg/L in adult RA patients with a dosage of 25 mg twice weekly and 2.1 mcg in pediatric JIA patients with a dosage of 0.4 mg/kg twice weekly. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Population pharmacokinetic modeling predicts a total Vd of 5.49 L with a peripheral compartment of 1.24 L in adults with RA and an apparent Vd with subcutaneous administration in pediatric JIA patients of 7.88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No significant protein binding has been identified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As etanercept is a fusion protein antibody, it is assumed to be metabolized via proteinases similarly to endogenous proteins. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Etanercept has a mean half-life of elimination of 102 hours in RA patients. Population models have shown a mean half-life of 68 hours in healthy adults and 70.7-94.8 hours in pediatric JIA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Etanercept has a mean apparent clearance of 160 mL/h in RA patients. Population models predict a mean apparent clearance of 132 mL/h in healthy adults and 0.0576 L/h in pediatric JIA patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Enbrel, Eticovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etanercept is a protein therapy based on the binding fragment of the tumour necrosis factor alpha receptor used to treat severe rheumatoid arthritis and moderate to severe plaque psoriasis.

Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Question: Does Abatacept and Etanercept interact? Information: •Drug A: Abatacept •Drug B: Etanercept •Severity: MAJOR •Description: The risk or severity of infection can be increased when Etanercept is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etanercept is indicated for the treatment of moderately to severely active rheumatoid arthritis in adults and in chronic moderate to severe plaque psoriasis in patients 4 years of age and older. It is also used to manage signs and symptoms of polyarticular idiopathic arthritis and Juvenile Psoriatic Arthritis in those aged 2 years and older. Etanercept is also used to manage the symptoms of psoriatic arthritis and ankylosing spondylitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etanercept binds specifically to tumor necrosis factor (TNF) and thereby modulates biological processes that are induced or regulated by TNF. Such processes or molecules affected include the level of adhesion molecules expressed, as well as serum levels of cytokines and matrix metalloproteinases. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There are two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75). The biological activity of TNF is dependent upon binding to either cell surface receptor (p75 or p55). Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules, thereby effectively removing them from circulation. Notably, etancerpt is only capable of binding to the active trimeric form of TNF as its binding site is located in the cleft between subunits. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Increased levels of TNF are found in tissues and fluids of those with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Population pharmacokinetic modeling in adults with RA, AS, or who were healthy showed a subcutaneous bioavailability of 56.9% with a Ka of 0.0223/h. Another model in pediatric JIA patients showed an increased Ka of 0.05/h with a high mean interindividual variability of 215%. Cmax after a single 25 mg subcutaneous dose of Enbrel is reported as 1.1 mcg/L with a Tmax of 69 h. Cmax after repeated dosing is reported as 2.4 mcg/L in adult RA patients with a dosage of 25 mg twice weekly and 2.1 mcg in pediatric JIA patients with a dosage of 0.4 mg/kg twice weekly. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Population pharmacokinetic modeling predicts a total Vd of 5.49 L with a peripheral compartment of 1.24 L in adults with RA and an apparent Vd with subcutaneous administration in pediatric JIA patients of 7.88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No significant protein binding has been identified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As etanercept is a fusion protein antibody, it is assumed to be metabolized via proteinases similarly to endogenous proteins. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Etanercept has a mean half-life of elimination of 102 hours in RA patients. Population models have shown a mean half-life of 68 hours in healthy adults and 70.7-94.8 hours in pediatric JIA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Etanercept has a mean apparent clearance of 160 mL/h in RA patients. Population models predict a mean apparent clearance of 132 mL/h in healthy adults and 0.0576 L/h in pediatric JIA patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Enbrel, Eticovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etanercept is a protein therapy based on the binding fragment of the tumour necrosis factor alpha receptor used to treat severe rheumatoid arthritis and moderate to severe plaque psoriasis. Output: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Does Abatacept and Ethanol interact?

•Drug A: Abatacept •Drug B: Ethanol •Severity: MODERATE •Description: The metabolism of Ethanol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For therapeutic neurolysis of nerves or ganglia for the relief of intractable chronic pain in such conditions as inoperable cancer and trigeminal neuralgia (tic douloureux), in patients for whom neurosurgical procedures are contraindicated. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Metabolized by cytochrome P450 enzyme CYP2E1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 5628 mg/kg. Symptoms and effects of overdose include nausea, vomiting, CNS depression, acute respiratory failure or death and with chronic use, severe health problems, such as liver and brain damage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmacol, Gattex, Healing Waters Aloe Cucumber Hand Sanitizer, Healing Waters Cotton Blossom Hand Sanitizer, Healing Waters Lemon Verbena Hand Sanitizer, Healing Waters Peach Nectarine Hand Sanitizer, Lupaneta Pack 1-month, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydroxyethane Alcohol Alcohol (ethyl) Alcohol denatured Alcohol etílico Alcohol, denatured Alcool éthylique Alkohol Äthanol Äthylalkohol Dehydrated alcohol Dehydrated ethanol etanol éthanol Ethyl Alcohol Grain alcohol Hydroxyethane Methylcarbinol Spiritus vini •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ethanol interact? Information: •Drug A: Abatacept •Drug B: Ethanol •Severity: MODERATE •Description: The metabolism of Ethanol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For therapeutic neurolysis of nerves or ganglia for the relief of intractable chronic pain in such conditions as inoperable cancer and trigeminal neuralgia (tic douloureux), in patients for whom neurosurgical procedures are contraindicated. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Metabolized by cytochrome P450 enzyme CYP2E1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 5628 mg/kg. Symptoms and effects of overdose include nausea, vomiting, CNS depression, acute respiratory failure or death and with chronic use, severe health problems, such as liver and brain damage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmacol, Gattex, Healing Waters Aloe Cucumber Hand Sanitizer, Healing Waters Cotton Blossom Hand Sanitizer, Healing Waters Lemon Verbena Hand Sanitizer, Healing Waters Peach Nectarine Hand Sanitizer, Lupaneta Pack 1-month, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydroxyethane Alcohol Alcohol (ethyl) Alcohol denatured Alcohol etílico Alcohol, denatured Alcool éthylique Alkohol Äthanol Äthylalkohol Dehydrated alcohol Dehydrated ethanol etanol éthanol Ethyl Alcohol Grain alcohol Hydroxyethane Methylcarbinol Spiritus vini •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Ethinylestradiol interact?

•Drug A: Abatacept •Drug B: Ethinylestradiol •Severity: MODERATE •Description: The metabolism of Ethinylestradiol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ethinylestradiol is combined with other drugs for use as a contraceptive, premenstrual dysphoric disorder, moderate acne, moderate to severe vasomotor symptoms of menopause, prevention of postmenopausal osteoporosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ethinylestradiol is a synthetic estrogen that decreases luteinizing hormone to decrease endometrial vascularization, and decreases gonadotrophic hormone to prevent ovulation. It has a long duration of action as it is taken once daily, and a wide therapeutic index as overdoses are generally not associated with serious adverse effects. Patients should be counselled regarding the risks of thrombotic events. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 30µg oral dose of ethinylestradiol reaches a C max of 74.1±35.6pg/mL, with a T max of 1.5±0.5h, and an AUC of 487.4±166.6pg*h/mL. A 1.2mg dose delivered via a patch reaches a C max of 28.8±10.3pg/mL, with a T max of 86±31h, and an AUC of3895±1423pg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): A 30µg oral dose has an apparent volume of distribution of 625.3±228.7L and a 1.2mg topical dose has an apparent volume of distribution of 11745.3±15934.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Enthinylestradiol is 98.3-98.5% bound to albumin in serum but also exhibits binding to sex hormone binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ethinylestradiol can be glucuronidated by UGT1A1, UGT1A3, UGT1A4, UGT1A9, and UGT2B7. Ethinylestradiol is also sulfated by SULT1A1, SULT1A3, and SULT1E1. Ethinylestradiol can also be hydroxylated at positions 2, 4, 6, 7, and 16 by CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP1A2. These hydroxylated metabolites can be methylated by catechol-O-methyltransferase. The methoxy metabolites can in turn be sulfated or glucuronidated. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ethinylestradiol is 59.2% eliminated in the urine and bile, while 2-3% is eliminated in the feces. Over 90% of ethinylestradiol is eliminated as the unchanged parent drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): A 30µg oral dose has a half life of 8.4±4.8h and a 1.2mg topical dose has a half life of 27.7±34.2h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Ethinylestradiol has an intravenous clearance of 16.47L/h, and an estimated renal clearance of approximately 2.1L/h. A 30µg oral dose has a clearance of 58.0±19.8L/h and a 1.2mg topical dose has a clearance of 303.5±100.5L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Female patients experiencing and overdose may present with withdrawal bleeding, nausea, vomiting, breast tenderness, abdominal pain, drowsiness, and fatigue. Overdose should be treated with symptomatic and supportive care including monitoring for potassium concentrations, sodium concentrations, and signs of metabolic acidosis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afirmelle 28 Day, Alesse, Altavera 28 Day, Alyacen 1/35, Alyacen 7/7/7, Amethia 91 Day, Amethyst, Annovera, Apri 28 Day, Aranelle 28, Ashlyna 91 Day, Aubra 28 Day, Aurovela, Aurovela Fe, Aviane 28, Ayuna 28 Day Pack, Azurette 28 Day, Balcoltra 28 Day, Balziva 28 Day, Bekyree 28 Day, Beyaz 28 Day, Blisovi 21 Fe 1.5/30 28 Day Pack, Blisovi 21 Fe 1/20 28 Day Pack, Blisovi 24 Fe 1/20 28 Day, Brevicon, Briellyn 28 Day, Camrese 91 Day, Camreselo 91 Day, Caziant 28 Day, Cesia 28 Day, Charlotte 24 Fe Chewable 28 Day, Chateal 28 Day, Cléo -35, Cryselle 28, Cyclafem 1/35 28 Day, Cyclafem 7/7/7 28 Day, Cyestra-35, Cyonanz 28 Day, Cyred 28 Day, Dasetta 1/35 28 Day, Dasetta 7/7/7 28 Day, Daysee 91 Day, Delyla 28 Day, Diane, Dolishale 28 Day, Elinest 28 Day, Eluryng, Emoquette, Enilloring, Enpresse 28 Day, Enskyce 28 Day, Estarylla 28 Day, Evra, Falmina 28 Day, Fayosim 91 Day, Femcon Fe 28 Day, Femhrt 0.5/2.5 28 Day, Femynor 28 Day, Finzala 24 Fe Chewable 28 Day, Freya, Fyavolv, Gemmily 28 Day, Gianvi 28-day, Hailey 1.5/30 21 Day, Hailey 24 Fe 28 Day, Hailey Fe 1.5/30 28 Day, Hailey Fe 1/20 28 Day, Iclevia 91 Day, Indayo, Introvale 91 Day, Isibloom 28 Day, Jaimiess 91 Day, Jasmiel 28 Day, Jinteli, Jolessa 91 Day, Joyeaux 28 Day, Juleber 28 Day, Junel 1.5/30 21 Day, Junel 1/20 21 Day, Junel Fe 1.5/30 28 Day, Junel Fe 1/20 28 Day, Junel Fe 24 1/20 28 Day, Kaitlib Fe 28 Day, Kalliga, Kariva 28 Day, Kelnor 1/35 28 Day, Kelnor 1/50 28 Day, Kurvelo, Larin 1.5/30, Larin 1/20, Larin 24 Fe 1/20, Larin Fe 1.5/30, Larin Fe 1/20, Layolis Fe 28, Leena 28 Day, Levonest 28 Day, Levora 0.15/30 28 Day, Linessa, Lo Loestrin Fe 28 Day, Lo Simpesse, Lo-zumandimine 28 Day, Lo/ovral 28 Day, LoJaimiess, Loestrin 1.5/30 21 Day, Loestrin 24 Fe 28 Day, Loestrin Fe 1/20 28 Day, Lolo, Lomedia 24 Fe, Loryna, Loseasonique, Low-ogestrel 28 Day, Lutera 28 Day, Marlissa 28 Day, Marvelon, Melodetta 24 Fe Chewable 28 Day, Merzee 28 Day, Mibelas 24 Fe Chewable 28 Day, Microgestin 1.5/30 21 Day, Microgestin 1/20 21 Day, Microgestin 24 Fe 28 Day, Microgestin Fe 1.5/30 28 Day, Microgestin Fe 1/20 28 Day, Mili 28 Day, Min-ovral, Minastrin 24 Fe Chewable 28 Day, Mircette 28 Day, Mono-linyah 28 Day, Mononessa 28 Day, Myzilra 28 Day, Necon 0.5/35 28 Day, Necon 1/35 28 Day, Necon 7/7/7 28 Day, Nexesta Fe 28 Day, Nikki 28 Day, Nortrel 1/35 21 Day, Nortrel 1/35 28 Day, Nortrel 7/7/7 28 Day, Nuvaring, Nylia 1/35 28 Day, Nylia 7/7/7 28 Day, Nymyo 28 Day, Ocella 28 Day, Orsythia 28 Day, Ortho Tri-cyclen 28 Day, Ortho Tri-cyclen Lo 28 Day, Ortho-novum 7/7/7 28 Day, Philith 28 Day, Pimtrea Pack, Pirmella 1/35 28 Day, Pirmella 7/7/7 28 Day, Portia 28 Day, Previfem 28 Day, Quartette 91 Day Pack, Reclipsen, Rhuzdah 28 Day, Rivelsa 91 Day, Safyral 28 Day, Seasonale, Seasonique, Select, Setlakin 91 Day, Simliya, Simpesse, Sprintec 28 Day, Sronyx 28 Day, Syeda 28 Day, Synphasic, Tarina 24 Fe 1/20 28 Day, Tarina Fe 1/20 28 Day, Taysofy 28 Day, Taytulla 28 Day, Tilia Fe, Tri Femynor 28 Day, Tri-LO- Estarylla 28 Day, Tri-LO-marzia 28-day, Tri-LO-mili, Tri-Lo-Sprintec, Tri-estarylla 28 Day, Tri-legest 28 Day, Tri-linyah, Tri-mili 28 Day, Tri-nymyo 28 Day Pack, Tri-previfem 28 Day, Tri-sprintec 28 Day, Tri-vylibra 28 Day, Tri-vylibra Lo 28 Day, Trinessa 28 Day, Trinessa Lo 28 Day, Triquilar, Trivora 28 Day, Turqoz 28 Day, Twirla 3 Count Weekly Patch, Tyblume 28 Day, Tydemy 28 Day, Velivet 28 Day, Vestura, Vienva 28 Day, Viorele 28 Day, Volnea 28 Day, Vyfemla 28 Day, Vylibra 28 Day, Wera 28 Day, Wymzya Fe 28 Day, Xulane, Yasmin, Yasmin 28 Day, Yaz 28 Day, Yaz Plus, Zafemy, Zarah, Zenchent, Zovia 1/35e 28 Day, Zovia 1/50e 28 Day, Zumandimine 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17-ethinylestradiol 17alpha-Ethinyl estradiol Ethinyl estradiol Ethinylestradiol Ethinylestradiolum Ethinyloestradiol Ethynyl estradiol Etinilestradiol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ethinylestradiol is an estradiol used as a contraceptive.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ethinylestradiol interact? Information: •Drug A: Abatacept •Drug B: Ethinylestradiol •Severity: MODERATE •Description: The metabolism of Ethinylestradiol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ethinylestradiol is combined with other drugs for use as a contraceptive, premenstrual dysphoric disorder, moderate acne, moderate to severe vasomotor symptoms of menopause, prevention of postmenopausal osteoporosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ethinylestradiol is a synthetic estrogen that decreases luteinizing hormone to decrease endometrial vascularization, and decreases gonadotrophic hormone to prevent ovulation. It has a long duration of action as it is taken once daily, and a wide therapeutic index as overdoses are generally not associated with serious adverse effects. Patients should be counselled regarding the risks of thrombotic events. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 30µg oral dose of ethinylestradiol reaches a C max of 74.1±35.6pg/mL, with a T max of 1.5±0.5h, and an AUC of 487.4±166.6pg*h/mL. A 1.2mg dose delivered via a patch reaches a C max of 28.8±10.3pg/mL, with a T max of 86±31h, and an AUC of3895±1423pg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): A 30µg oral dose has an apparent volume of distribution of 625.3±228.7L and a 1.2mg topical dose has an apparent volume of distribution of 11745.3±15934.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Enthinylestradiol is 98.3-98.5% bound to albumin in serum but also exhibits binding to sex hormone binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ethinylestradiol can be glucuronidated by UGT1A1, UGT1A3, UGT1A4, UGT1A9, and UGT2B7. Ethinylestradiol is also sulfated by SULT1A1, SULT1A3, and SULT1E1. Ethinylestradiol can also be hydroxylated at positions 2, 4, 6, 7, and 16 by CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP1A2. These hydroxylated metabolites can be methylated by catechol-O-methyltransferase. The methoxy metabolites can in turn be sulfated or glucuronidated. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ethinylestradiol is 59.2% eliminated in the urine and bile, while 2-3% is eliminated in the feces. Over 90% of ethinylestradiol is eliminated as the unchanged parent drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): A 30µg oral dose has a half life of 8.4±4.8h and a 1.2mg topical dose has a half life of 27.7±34.2h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Ethinylestradiol has an intravenous clearance of 16.47L/h, and an estimated renal clearance of approximately 2.1L/h. A 30µg oral dose has a clearance of 58.0±19.8L/h and a 1.2mg topical dose has a clearance of 303.5±100.5L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Female patients experiencing and overdose may present with withdrawal bleeding, nausea, vomiting, breast tenderness, abdominal pain, drowsiness, and fatigue. Overdose should be treated with symptomatic and supportive care including monitoring for potassium concentrations, sodium concentrations, and signs of metabolic acidosis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afirmelle 28 Day, Alesse, Altavera 28 Day, Alyacen 1/35, Alyacen 7/7/7, Amethia 91 Day, Amethyst, Annovera, Apri 28 Day, Aranelle 28, Ashlyna 91 Day, Aubra 28 Day, Aurovela, Aurovela Fe, Aviane 28, Ayuna 28 Day Pack, Azurette 28 Day, Balcoltra 28 Day, Balziva 28 Day, Bekyree 28 Day, Beyaz 28 Day, Blisovi 21 Fe 1.5/30 28 Day Pack, Blisovi 21 Fe 1/20 28 Day Pack, Blisovi 24 Fe 1/20 28 Day, Brevicon, Briellyn 28 Day, Camrese 91 Day, Camreselo 91 Day, Caziant 28 Day, Cesia 28 Day, Charlotte 24 Fe Chewable 28 Day, Chateal 28 Day, Cléo -35, Cryselle 28, Cyclafem 1/35 28 Day, Cyclafem 7/7/7 28 Day, Cyestra-35, Cyonanz 28 Day, Cyred 28 Day, Dasetta 1/35 28 Day, Dasetta 7/7/7 28 Day, Daysee 91 Day, Delyla 28 Day, Diane, Dolishale 28 Day, Elinest 28 Day, Eluryng, Emoquette, Enilloring, Enpresse 28 Day, Enskyce 28 Day, Estarylla 28 Day, Evra, Falmina 28 Day, Fayosim 91 Day, Femcon Fe 28 Day, Femhrt 0.5/2.5 28 Day, Femynor 28 Day, Finzala 24 Fe Chewable 28 Day, Freya, Fyavolv, Gemmily 28 Day, Gianvi 28-day, Hailey 1.5/30 21 Day, Hailey 24 Fe 28 Day, Hailey Fe 1.5/30 28 Day, Hailey Fe 1/20 28 Day, Iclevia 91 Day, Indayo, Introvale 91 Day, Isibloom 28 Day, Jaimiess 91 Day, Jasmiel 28 Day, Jinteli, Jolessa 91 Day, Joyeaux 28 Day, Juleber 28 Day, Junel 1.5/30 21 Day, Junel 1/20 21 Day, Junel Fe 1.5/30 28 Day, Junel Fe 1/20 28 Day, Junel Fe 24 1/20 28 Day, Kaitlib Fe 28 Day, Kalliga, Kariva 28 Day, Kelnor 1/35 28 Day, Kelnor 1/50 28 Day, Kurvelo, Larin 1.5/30, Larin 1/20, Larin 24 Fe 1/20, Larin Fe 1.5/30, Larin Fe 1/20, Layolis Fe 28, Leena 28 Day, Levonest 28 Day, Levora 0.15/30 28 Day, Linessa, Lo Loestrin Fe 28 Day, Lo Simpesse, Lo-zumandimine 28 Day, Lo/ovral 28 Day, LoJaimiess, Loestrin 1.5/30 21 Day, Loestrin 24 Fe 28 Day, Loestrin Fe 1/20 28 Day, Lolo, Lomedia 24 Fe, Loryna, Loseasonique, Low-ogestrel 28 Day, Lutera 28 Day, Marlissa 28 Day, Marvelon, Melodetta 24 Fe Chewable 28 Day, Merzee 28 Day, Mibelas 24 Fe Chewable 28 Day, Microgestin 1.5/30 21 Day, Microgestin 1/20 21 Day, Microgestin 24 Fe 28 Day, Microgestin Fe 1.5/30 28 Day, Microgestin Fe 1/20 28 Day, Mili 28 Day, Min-ovral, Minastrin 24 Fe Chewable 28 Day, Mircette 28 Day, Mono-linyah 28 Day, Mononessa 28 Day, Myzilra 28 Day, Necon 0.5/35 28 Day, Necon 1/35 28 Day, Necon 7/7/7 28 Day, Nexesta Fe 28 Day, Nikki 28 Day, Nortrel 1/35 21 Day, Nortrel 1/35 28 Day, Nortrel 7/7/7 28 Day, Nuvaring, Nylia 1/35 28 Day, Nylia 7/7/7 28 Day, Nymyo 28 Day, Ocella 28 Day, Orsythia 28 Day, Ortho Tri-cyclen 28 Day, Ortho Tri-cyclen Lo 28 Day, Ortho-novum 7/7/7 28 Day, Philith 28 Day, Pimtrea Pack, Pirmella 1/35 28 Day, Pirmella 7/7/7 28 Day, Portia 28 Day, Previfem 28 Day, Quartette 91 Day Pack, Reclipsen, Rhuzdah 28 Day, Rivelsa 91 Day, Safyral 28 Day, Seasonale, Seasonique, Select, Setlakin 91 Day, Simliya, Simpesse, Sprintec 28 Day, Sronyx 28 Day, Syeda 28 Day, Synphasic, Tarina 24 Fe 1/20 28 Day, Tarina Fe 1/20 28 Day, Taysofy 28 Day, Taytulla 28 Day, Tilia Fe, Tri Femynor 28 Day, Tri-LO- Estarylla 28 Day, Tri-LO-marzia 28-day, Tri-LO-mili, Tri-Lo-Sprintec, Tri-estarylla 28 Day, Tri-legest 28 Day, Tri-linyah, Tri-mili 28 Day, Tri-nymyo 28 Day Pack, Tri-previfem 28 Day, Tri-sprintec 28 Day, Tri-vylibra 28 Day, Tri-vylibra Lo 28 Day, Trinessa 28 Day, Trinessa Lo 28 Day, Triquilar, Trivora 28 Day, Turqoz 28 Day, Twirla 3 Count Weekly Patch, Tyblume 28 Day, Tydemy 28 Day, Velivet 28 Day, Vestura, Vienva 28 Day, Viorele 28 Day, Volnea 28 Day, Vyfemla 28 Day, Vylibra 28 Day, Wera 28 Day, Wymzya Fe 28 Day, Xulane, Yasmin, Yasmin 28 Day, Yaz 28 Day, Yaz Plus, Zafemy, Zarah, Zenchent, Zovia 1/35e 28 Day, Zovia 1/50e 28 Day, Zumandimine 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17-ethinylestradiol 17alpha-Ethinyl estradiol Ethinyl estradiol Ethinylestradiol Ethinylestradiolum Ethinyloestradiol Ethynyl estradiol Etinilestradiol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ethinylestradiol is an estradiol used as a contraceptive. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Ethosuximide interact?

•Drug A: Abatacept •Drug B: Ethosuximide •Severity: MODERATE •Description: The metabolism of Ethosuximide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of petit mal epilepsy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability following oral administration is 93%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, via CYP3A4 and CYP2E1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 53 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zarontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aethosuximide Atysmal Ethosuximid Ethosuximide éthosuximide Ethosuximidum Etosuximida Thilopemal •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ethosuximide is an anticonvulsant used to treat petit mal seizures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ethosuximide interact? Information: •Drug A: Abatacept •Drug B: Ethosuximide •Severity: MODERATE •Description: The metabolism of Ethosuximide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of petit mal epilepsy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability following oral administration is 93%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, via CYP3A4 and CYP2E1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 53 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zarontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aethosuximide Atysmal Ethosuximid Ethosuximide éthosuximide Ethosuximidum Etosuximida Thilopemal •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ethosuximide is an anticonvulsant used to treat petit mal seizures. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Does Abatacept and Etodolac interact?

•Drug A: Abatacept •Drug B: Etodolac •Severity: MODERATE •Description: The metabolism of Etodolac can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion in vivo. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 390 mL/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99% bound, primarily to albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Etodolac is extensively metabolized in the liver. Renal elimination of etodolac and its metabolites is the primary route of excretion (72%). Metabolites found in urine (with percents of the administered dose) are: unchanged etodolac (1%), etodolac glucuronide (13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal excretion accounts for 16% of its elimination. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Terminal t 1/2, 7.3 ± 4.0 hours. Distribution t 1/2, 0.71 ± 0.50 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral cl=49.1 mL/h/kg [Normal healthy adults] Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)] Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)] Oral cl=45.7 mL/h/kg [Eldery (>65 years)] Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)] Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of etodolac. Etodolac may increase blood pressure and/or cause fluid retention and edema. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lodine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etodolac Étodolac Etodolaco Etodolacum Etodolic acid Etodolsäure •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etodolac is an NSAID used to treat osteoarthritis and rheumatoid arthritis, as well as acute pain.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Etodolac interact? Information: •Drug A: Abatacept •Drug B: Etodolac •Severity: MODERATE •Description: The metabolism of Etodolac can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion in vivo. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 390 mL/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99% bound, primarily to albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Etodolac is extensively metabolized in the liver. Renal elimination of etodolac and its metabolites is the primary route of excretion (72%). Metabolites found in urine (with percents of the administered dose) are: unchanged etodolac (1%), etodolac glucuronide (13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal excretion accounts for 16% of its elimination. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Terminal t 1/2, 7.3 ± 4.0 hours. Distribution t 1/2, 0.71 ± 0.50 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral cl=49.1 mL/h/kg [Normal healthy adults] Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)] Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)] Oral cl=45.7 mL/h/kg [Eldery (>65 years)] Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)] Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of etodolac. Etodolac may increase blood pressure and/or cause fluid retention and edema. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lodine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etodolac Étodolac Etodolaco Etodolacum Etodolic acid Etodolsäure •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etodolac is an NSAID used to treat osteoarthritis and rheumatoid arthritis, as well as acute pain. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Etoposide interact?

•Drug A: Abatacept •Drug B: Etoposide •Severity: MAJOR •Description: The metabolism of Etoposide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The disposition of etoposide is a biphasic process with a distribution half-life of 1.5 hours. It does not cross into cerebrospinal fluid well. Volume of distribution, steady state = 18 - 29 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. 56% of the dose was in the urine, 45% of which was excreted as etoposide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 4-11 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total body clearance = 33 - 48 mL/min [IV administration, adults] Mean renal clearance = 7 - 10 mL/min/m^2 •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Etopophos, Vepesid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etoposide Etoposido Etoposidum trans-Etoposide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etoposide is a podophyllotoxin derivative used to treat testicular and small cell lung tumors.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Etoposide interact? Information: •Drug A: Abatacept •Drug B: Etoposide •Severity: MAJOR •Description: The metabolism of Etoposide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The disposition of etoposide is a biphasic process with a distribution half-life of 1.5 hours. It does not cross into cerebrospinal fluid well. Volume of distribution, steady state = 18 - 29 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. 56% of the dose was in the urine, 45% of which was excreted as etoposide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 4-11 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total body clearance = 33 - 48 mL/min [IV administration, adults] Mean renal clearance = 7 - 10 mL/min/m^2 •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Etopophos, Vepesid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etoposide Etoposido Etoposidum trans-Etoposide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etoposide is a podophyllotoxin derivative used to treat testicular and small cell lung tumors. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Etoricoxib interact?

•Drug A: Abatacept •Drug B: Etoricoxib •Severity: MODERATE •Description: The metabolism of Etoricoxib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etoricoxib is a COX-2 selective inhibitor (approximately 106 times more selective for COX-2 inhibition over COX-1). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Like any other COX-2 selective inhibitor Etoricoxib selectively inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2), preventing production of prostaglandins (PGs) from arachidonic acid. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability is 100% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, primarily via CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 22 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): This reduced activity is the cause of reduced gastrointestinal toxicity, as demonstrated in several large clinical trials performed with different COXIB (see below links on NEJM and The Lancet). Some clinical trials and meta-analysis showed that treatment with COXIB lead to increased incidence of cardiovascular adverse events compared to placebo •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etoricoxib étoricoxib Etoricoxibum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etoricoxib is a selective COX-2 inhibitor used to relieve moderate post-surgical dental pain as a short-term treatment and inflammatory and painful symptoms of various forms of arthritis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Etoricoxib interact? Information: •Drug A: Abatacept •Drug B: Etoricoxib •Severity: MODERATE •Description: The metabolism of Etoricoxib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etoricoxib is a COX-2 selective inhibitor (approximately 106 times more selective for COX-2 inhibition over COX-1). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Like any other COX-2 selective inhibitor Etoricoxib selectively inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2), preventing production of prostaglandins (PGs) from arachidonic acid. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability is 100% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, primarily via CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 22 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): This reduced activity is the cause of reduced gastrointestinal toxicity, as demonstrated in several large clinical trials performed with different COXIB (see below links on NEJM and The Lancet). Some clinical trials and meta-analysis showed that treatment with COXIB lead to increased incidence of cardiovascular adverse events compared to placebo •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Etoricoxib étoricoxib Etoricoxibum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etoricoxib is a selective COX-2 inhibitor used to relieve moderate post-surgical dental pain as a short-term treatment and inflammatory and painful symptoms of various forms of arthritis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Etrasimod interact?

•Drug A: Abatacept •Drug B: Etrasimod •Severity: MODERATE •Description: The risk or severity of immunosuppression can be increased when Abatacept is combined with Etrasimod. •Extended Description: Etrasimod has been known to cause immunosuppression due to the sequestration of peripheral blood lymphocytes due to the modulation of the S1P receptors. Therefore, the co-administration of etrasimod with other immunosuppressive agents can increase the risk of additive immunosuppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etrasimod causes a reduction in peripheral blood lymphocyte count. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with etrasimod. Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing etrasimod 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks. Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of etrasimod on Day 1. At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation. Reductions in absolute FEV1 were also observed in subjects treated with etrasimod. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P 1,4,5 ). Etrasimod has minimal activity on S1P 3 (25-fold lower than C max at the recommended dose) and no activity on S1P 2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Etrasimod mean (SD) steady-state maximum plasma concentration (C max ) was 113 (27.5) ng/mL and the area under the time concentration curve at the dosing interval (AUC tau ) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod C max and AUC are approximately dose-proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose. The median (range) time to reach etrasimod C max (T max ) is approximately 4 hours (range 2 to 8 hours) after oral administration. No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of etrasimod with a high-fat meal (800 to 1000 calories). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution of etrasimod is 66 (24) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Etrasimod plasma protein binding is 97.9%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 82% of the total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of the administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean plasma elimination half-life (t 1/2 ) of etrasimod is approximately 30 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent steady-state oral clearance of etrasimod is approximately 1 L/h after oral administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the maximum recommended human dose (MRHD) of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (7 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (7 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD). In a pre-and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD). Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at MRHD). Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays. Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Velsipity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etrasimod is an S1P receptors modulator used to treat moderate to severely active ulcerative colitis in adults

Etrasimod has been known to cause immunosuppression due to the sequestration of peripheral blood lymphocytes due to the modulation of the S1P receptors. Therefore, the co-administration of etrasimod with other immunosuppressive agents can increase the risk of additive immunosuppression. The severity of the interaction is moderate.

Question: Does Abatacept and Etrasimod interact? Information: •Drug A: Abatacept •Drug B: Etrasimod •Severity: MODERATE •Description: The risk or severity of immunosuppression can be increased when Abatacept is combined with Etrasimod. •Extended Description: Etrasimod has been known to cause immunosuppression due to the sequestration of peripheral blood lymphocytes due to the modulation of the S1P receptors. Therefore, the co-administration of etrasimod with other immunosuppressive agents can increase the risk of additive immunosuppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etrasimod is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Etrasimod causes a reduction in peripheral blood lymphocyte count. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with etrasimod. Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing etrasimod 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks. Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of etrasimod on Day 1. At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation. Reductions in absolute FEV1 were also observed in subjects treated with etrasimod. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P 1,4,5 ). Etrasimod has minimal activity on S1P 3 (25-fold lower than C max at the recommended dose) and no activity on S1P 2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Etrasimod mean (SD) steady-state maximum plasma concentration (C max ) was 113 (27.5) ng/mL and the area under the time concentration curve at the dosing interval (AUC tau ) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod C max and AUC are approximately dose-proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose. The median (range) time to reach etrasimod C max (T max ) is approximately 4 hours (range 2 to 8 hours) after oral administration. No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of etrasimod with a high-fat meal (800 to 1000 calories). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution of etrasimod is 66 (24) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Etrasimod plasma protein binding is 97.9%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 82% of the total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of the administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean plasma elimination half-life (t 1/2 ) of etrasimod is approximately 30 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent steady-state oral clearance of etrasimod is approximately 1 L/h after oral administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings from animal studies, etrasimod may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with etrasimod are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. In an embryo-fetal development study in pregnant rats, etrasimod was orally administered at 1, 2, or 4 mg/kg/day (5, 11, and 21 times the exposure at the maximum recommended human dose (MRHD) of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 6 to 17. No maternal toxicity was observed up to 21 times the exposure at the MRHD. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 4 mg/kg/day (21 times the exposure at the MRHD). Etrasimod-related fetal external and/or visceral malformations were noted at all dose levels (≥5 times the exposure at the MRHD). In an embryo-fetal development study in pregnant rabbits, etrasimod was orally administered at 2, 10, or 20 mg/kg/day (0.8, 6, and 11 times the exposure at the MRHD of 2 mg, based on AUC comparison) during the period of organogenesis, from gestation day 7 to 20. Increased post-implantation loss with a corresponding decrease in the number of viable fetuses was observed at 10 and 20 mg/kg/day (7 and 11 times the exposure at the MRHD). Etrasimod-related fetal malformations including aortic arch defects and fused sternebrae were noted at 10 and/or 20 mg/kg/day (7 and 11 times the exposure at the MRHD). There were no adverse effects on embryofetal development at 2 mg/kg/day (less than the exposure at the MRHD). In a pre-and post-natal development study in rats, etrasimod was orally administered at 0.4, 2, or 4 mg/kg/day (2, 10, and 24 times the exposure at the MRHD of 2 mg, based on AUC comparison) throughout pregnancy and lactation, from gestation day 6 through lactation day 20. Mortality during delivery and impaired maternal performance including increased post-implantation loss, increased number of females with stillborn pups, increased number of stillborn pups per litter, decreased viability index, and/or decreased lactation index was observed at 2 and 4 mg/kg/day (10 and 24 times the exposure at the MRHD). Etrasimod was detected in the plasma of F1 offspring, indicating exposure from the milk of the lactating dam. Decreased pup body weights were observed during the preweaning period at all dose levels (maternal exposures ≥2 times the exposure at the MRHD), and decreased pup viability was observed at 2 and 4 mg/kg/day (maternal exposures 10 and 24 times the exposure at the MRHD). Reduced fertility and reproductive performance including reduction in implantations and increased preimplantation loss in F1 offspring occurred at the highest dose tested (maternal exposures 24 times the exposure at the MRHD). Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at MRHD). Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays. Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Velsipity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etrasimod is an S1P receptors modulator used to treat moderate to severely active ulcerative colitis in adults Output: Etrasimod has been known to cause immunosuppression due to the sequestration of peripheral blood lymphocytes due to the modulation of the S1P receptors. Therefore, the co-administration of etrasimod with other immunosuppressive agents can increase the risk of additive immunosuppression. The severity of the interaction is moderate.

Does Abatacept and Etravirine interact?

•Drug A: Abatacept •Drug B: Etravirine •Severity: MODERATE •Description: The metabolism of Etravirine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced patients ≥2 years of age. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Clinical trials have shown no prolongation of QT intervals on electrocardiograms after 8 days of dosing. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1). It directly binds reverse transcriptase and consequently blocks DNA-dependent and RNA-dependent polymerase activity. Etravirine does not inhibit human DNA polymerase alpha, beta or gamma. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Maximum oral absorption is achieved in 2.5-4 hours. Absorption is unaffected by the concomitant use of oral ranitidine or omeprazole, which decrease gastric acidity. Administration under fasting conditions resulted in a near 50% decrease in systemic exposure (AUC) when compared to administration after a meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Distribution of etravirine into compartments other than plasma has not been evaluated in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is about 99.9% in vitro. In vitro, 99.6% is bound to albumin, and 97.66% - 99.02% is bound to 1-alpha glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized (in vitro) by the liver CYP450 enzymes: CYP3A4, CYP2C9, CYP2C19. The major metabolites formed by a methyl hydroxylation of the dimethylbenzonitrile moiety retained less than 90% of etravirine's activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a 800mg dose of radio-labelled etraverine, 93.7% was found to undergo fecal elimination, with 81.2% - 86.4% eliminated unchanged. 1.2% of the dose was renally eliminated, changed. Etravirine is dialyzable (hemodialysis). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half life of 9.05-41 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal clearance of etravirine is negligible (<1.2%), thus no dose adjustments are required in patients with renal impairment. Clearance is shown to be reduced in patients with Hepatitis B and/or co-infection, however, the safety profile of etravirine does not call for dosage adjustments. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Intelence •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infections in combination with other antiretroviral agents.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Etravirine interact? Information: •Drug A: Abatacept •Drug B: Etravirine •Severity: MODERATE •Description: The metabolism of Etravirine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Etravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced patients ≥2 years of age. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Clinical trials have shown no prolongation of QT intervals on electrocardiograms after 8 days of dosing. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Etravirine exerts its effects via direct inhibition of the reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1). It directly binds reverse transcriptase and consequently blocks DNA-dependent and RNA-dependent polymerase activity. Etravirine does not inhibit human DNA polymerase alpha, beta or gamma. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Maximum oral absorption is achieved in 2.5-4 hours. Absorption is unaffected by the concomitant use of oral ranitidine or omeprazole, which decrease gastric acidity. Administration under fasting conditions resulted in a near 50% decrease in systemic exposure (AUC) when compared to administration after a meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Distribution of etravirine into compartments other than plasma has not been evaluated in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is about 99.9% in vitro. In vitro, 99.6% is bound to albumin, and 97.66% - 99.02% is bound to 1-alpha glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized (in vitro) by the liver CYP450 enzymes: CYP3A4, CYP2C9, CYP2C19. The major metabolites formed by a methyl hydroxylation of the dimethylbenzonitrile moiety retained less than 90% of etravirine's activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a 800mg dose of radio-labelled etraverine, 93.7% was found to undergo fecal elimination, with 81.2% - 86.4% eliminated unchanged. 1.2% of the dose was renally eliminated, changed. Etravirine is dialyzable (hemodialysis). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half life of 9.05-41 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal clearance of etravirine is negligible (<1.2%), thus no dose adjustments are required in patients with renal impairment. Clearance is shown to be reduced in patients with Hepatitis B and/or co-infection, however, the safety profile of etravirine does not call for dosage adjustments. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Intelence •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infections in combination with other antiretroviral agents. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Everolimus interact?

•Drug A: Abatacept •Drug B: Everolimus •Severity: MAJOR •Description: The metabolism of Everolimus can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The blood-to-plasma ratio of everolimus is 17% to 73%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~ 74% in both healthy patients and those with moderate hepatic impairment. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): ~30 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): IC50 of 0.63 nM. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afinitor, Votubia, Zortress •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Everolimus évérolimus •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Everolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor used to treat various types of malignancies.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Everolimus interact? Information: •Drug A: Abatacept •Drug B: Everolimus •Severity: MAJOR •Description: The metabolism of Everolimus can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The blood-to-plasma ratio of everolimus is 17% to 73%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~ 74% in both healthy patients and those with moderate hepatic impairment. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): ~30 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): IC50 of 0.63 nM. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afinitor, Votubia, Zortress •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Everolimus évérolimus •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Everolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor used to treat various types of malignancies. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Fedratinib interact?

•Drug A: Abatacept •Drug B: Fedratinib •Severity: MODERATE •Description: The metabolism of Fedratinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fedratinib is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fedratinib is a kinase inhibitor that inhibits cell division and induces apoptosis. Patients taking fedratinib may experience anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, or elevated amylase and lipase. These effects should be managed by reducing the dose, temporarily stopping the medication, or providing transfusions on a case by case basis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3. JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis. Fedratinib's inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 400mg oral dose results in a C max of 1804ng/mL and an AUC of 26,870ng/*hr/mL. Fedratinib has a T max of 1.75-3 hours. A high fat breakfast does not significantly affect the absorption of fedratinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution is 1770L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fedratinib is ≥92% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3. Beyond that, data regarding the metabolism of fedratinib is not readily available. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): An oral dose of fedratinib is 77% eliminated in the feces with 23% as unchanged drug. 5% is eliminated in the urine, with 3% as unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fedratinib is 41 hours with a terminal half life of 114 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of fedratinib is 13L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Data regarding fedratinib in overdose is not readily available. Patients given 680mg/day experienced a greater incidence and severity of adverse effects including anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and elevated amylase and lipase. These effects were treated symptomatically as well as by reducing the dose or temporarily stopping fedratinib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inrebic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fedratinib interact? Information: •Drug A: Abatacept •Drug B: Fedratinib •Severity: MODERATE •Description: The metabolism of Fedratinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fedratinib is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fedratinib is a kinase inhibitor that inhibits cell division and induces apoptosis. Patients taking fedratinib may experience anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, or elevated amylase and lipase. These effects should be managed by reducing the dose, temporarily stopping the medication, or providing transfusions on a case by case basis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3. JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis. Fedratinib's inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 400mg oral dose results in a C max of 1804ng/mL and an AUC of 26,870ng/*hr/mL. Fedratinib has a T max of 1.75-3 hours. A high fat breakfast does not significantly affect the absorption of fedratinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution is 1770L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fedratinib is ≥92% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3. Beyond that, data regarding the metabolism of fedratinib is not readily available. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): An oral dose of fedratinib is 77% eliminated in the feces with 23% as unchanged drug. 5% is eliminated in the urine, with 3% as unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fedratinib is 41 hours with a terminal half life of 114 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of fedratinib is 13L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Data regarding fedratinib in overdose is not readily available. Patients given 680mg/day experienced a greater incidence and severity of adverse effects including anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and elevated amylase and lipase. These effects were treated symptomatically as well as by reducing the dose or temporarily stopping fedratinib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inrebic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Felbamate interact?

•Drug A: Abatacept •Drug B: Felbamate •Severity: MODERATE •Description: The metabolism of Felbamate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Felbamate is an antiepileptic indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures resulting from epilepsy. Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. In vitro receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): >90% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 756±82 mL/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20-36% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20-23 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 26 +/- 3 mL/hr/kg [single 1200 mg dose] 30 +/- 8 mL/hr/kg [multiple daily doses of 3600 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =5000 mg/kg (Orally in rats) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Felbatol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felbamate Felbamato Felbamatum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Felbamate is an anticonvulsant used to treat severe epilepsy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Felbamate interact? Information: •Drug A: Abatacept •Drug B: Felbamate •Severity: MODERATE •Description: The metabolism of Felbamate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Felbamate is an antiepileptic indicated as monotherapy or as an adjunct to other anticonvulsants for the treatment of partial seizures resulting from epilepsy. Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. In vitro receptor binding studies suggest that felbamate may be an antagonist at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. Antagonism of the NMDA receptor glycine binding site may block the effects of the excitatory amino acids and suppress seizure activity. Animal studies indicate that felbamate may increase the seizure threshold and may decrease seizure spread. It is also indicated that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): >90% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 756±82 mL/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20-36% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20-23 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 26 +/- 3 mL/hr/kg [single 1200 mg dose] 30 +/- 8 mL/hr/kg [multiple daily doses of 3600 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =5000 mg/kg (Orally in rats) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Felbatol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felbamate Felbamato Felbamatum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Felbamate is an anticonvulsant used to treat severe epilepsy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2E1 substrates. The severity of the interaction is moderate.

Does Abatacept and Felodipine interact?

•Drug A: Abatacept •Drug B: Felodipine •Severity: MODERATE •Description: The metabolism of Felodipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Felodipine interact? Information: •Drug A: Abatacept •Drug B: Felodipine •Severity: MODERATE •Description: The metabolism of Felodipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Fenfluramine interact?

•Drug A: Abatacept •Drug B: Fenfluramine •Severity: MODERATE •Description: The metabolism of Fenfluramine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients aged two years and older. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fenfluramine increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT 2 receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit. This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Fenfluramine should be gradually withdrawn following treatment alteration or cessation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions. Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the SCN1A gene, which encodes the alpha subunit of a voltage-gated sodium channel (Na v 1.1). This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome. Various in vitro and in vivo studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT 1A, 5-HT 1D, 5-HT 2A, 5-HT 2B, and 5-HT 2C, as well as a σ1 receptor antagonist. This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels. However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT 1D, 5-HT 2C, σ1, and possibly 5-HT 2A receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT 2B receptor agonism, which had previously been associated with cardiac valvulopathy, is not anticipated to have any therapeutic value in Dravet syndrome. Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT 1D and 5-HT 2C may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to N -methyl-D-aspartate (NMDA). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fenfluramine has a steady-state T max of between four and five hours and an absolute bioavailability of approximately 68-74%. Fenfluramine administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean C max of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC 0-24 was 1390 (44%) ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Fenfluramine has an apparent volume of distribution of 11.9 L/kg with a coefficient of variation of 16.5% following oral administration in healthy subjects. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fenfluramine is 50% bound to plasma proteins independent of plasma drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fenfluramine is metabolized primarily in the liver by CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 to yield the major active metabolite norfenfluramine and several other minor inactive metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Over 90% of fenfluramine is excreted in urine and less than 5% in feces; unchanged fenfluramine and the major active metabolite norfenfluramine account for less than 25% of the recovered amount. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fenfluramine has an elimination half-life of 20 hours in healthy subjects. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fenfluramine has a mean clearance of 24.8 L/h with a coefficient of variation of 29% in healthy subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdosage of fenfluramine has been reported; in overdose cases, symptoms include agitation, anxiety, restlessness, twitching, tremors/muscle spasms, flushing, tachycardia, mydriasis, increased muscle tone, respiratory distress/failure, seizure, and coma. Some overdosage cases proved fatal, and in most fatal cases, patients experienced seizures, coma, and cardiorespiratory arrest. There is currently no standard practice for managing fenfluramine overdose. Symptomatic management, including ensuring proper ventilation and monitoring of both cardiac and respiratory functions is recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fintepla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fenfluramina Fenfluramine Fenfluraminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fenfluramine is fenfluramine is a phenethylamine that is structurally similar to serotonin. Due to its ability to increase extracellular serotonin levels, modulate serotonergic and other neurologic receptors, and control neurotransmission, it is effective in treating pharmacoresistant seizures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fenfluramine interact? Information: •Drug A: Abatacept •Drug B: Fenfluramine •Severity: MODERATE •Description: The metabolism of Fenfluramine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients aged two years and older. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fenfluramine increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT 2 receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit. This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Fenfluramine should be gradually withdrawn following treatment alteration or cessation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions. Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the SCN1A gene, which encodes the alpha subunit of a voltage-gated sodium channel (Na v 1.1). This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome. Various in vitro and in vivo studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT 1A, 5-HT 1D, 5-HT 2A, 5-HT 2B, and 5-HT 2C, as well as a σ1 receptor antagonist. This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels. However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT 1D, 5-HT 2C, σ1, and possibly 5-HT 2A receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT 2B receptor agonism, which had previously been associated with cardiac valvulopathy, is not anticipated to have any therapeutic value in Dravet syndrome. Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT 1D and 5-HT 2C may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to N -methyl-D-aspartate (NMDA). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fenfluramine has a steady-state T max of between four and five hours and an absolute bioavailability of approximately 68-74%. Fenfluramine administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean C max of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC 0-24 was 1390 (44%) ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Fenfluramine has an apparent volume of distribution of 11.9 L/kg with a coefficient of variation of 16.5% following oral administration in healthy subjects. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fenfluramine is 50% bound to plasma proteins independent of plasma drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fenfluramine is metabolized primarily in the liver by CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 to yield the major active metabolite norfenfluramine and several other minor inactive metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Over 90% of fenfluramine is excreted in urine and less than 5% in feces; unchanged fenfluramine and the major active metabolite norfenfluramine account for less than 25% of the recovered amount. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fenfluramine has an elimination half-life of 20 hours in healthy subjects. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fenfluramine has a mean clearance of 24.8 L/h with a coefficient of variation of 29% in healthy subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdosage of fenfluramine has been reported; in overdose cases, symptoms include agitation, anxiety, restlessness, twitching, tremors/muscle spasms, flushing, tachycardia, mydriasis, increased muscle tone, respiratory distress/failure, seizure, and coma. Some overdosage cases proved fatal, and in most fatal cases, patients experienced seizures, coma, and cardiorespiratory arrest. There is currently no standard practice for managing fenfluramine overdose. Symptomatic management, including ensuring proper ventilation and monitoring of both cardiac and respiratory functions is recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fintepla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fenfluramina Fenfluramine Fenfluraminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fenfluramine is fenfluramine is a phenethylamine that is structurally similar to serotonin. Due to its ability to increase extracellular serotonin levels, modulate serotonergic and other neurologic receptors, and control neurotransmission, it is effective in treating pharmacoresistant seizures. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Fenofibrate interact?

•Drug A: Abatacept •Drug B: Fenofibrate •Severity: MODERATE •Description: The metabolism of Fenofibrate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fenofibrate is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides, and Apo B, and to increase HDL-C adults with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate is also indicated to treat adults with severe hypertriglyceridemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A single 300mg oral dose of fenofibrate reaches a C max of 6-9.5mg/L with a T max of 4-6h in healthy, fasting volunteers. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fenofibrate is 0.89L/kg, and can be as high as 60L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fenofibrate is 99% protein bound in serum, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fenofibric acid, the active metabolite of fenofibrate, has a half life of 23 hours. Fenofibrate has a half life of 19-27 hours in healthy subjects and up to 143 hours in patients with renal failure. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance of fenofibrate is 1.1L/h in young adults and 1.2L/h in the elderly. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is >2g/kg and in mice is 1600mg/kg. The oral TDLO in rats is 9mg/kg. Treat patients with supportive care including monitoring of vital signs and observing clinical status. Recent overdose may be treated with inducing vomiting or gastric lavage. Due to fenofibrate's extensive protein binding, hemodialysis is not expected to be useful. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Antara, Cholib, Fenoglide, Fenomax, Lipidil Supra, Lipofen, Tricor, Triglide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fenofibrate Fenofibrato Fenofibratum Finofibrate Procetofen •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fenofibrate is a peroxisome proliferator receptor alpha activator used to lower LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C in hypercholesterolemia, dyslipidemia, and hypertriglyceridemia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fenofibrate interact? Information: •Drug A: Abatacept •Drug B: Fenofibrate •Severity: MODERATE •Description: The metabolism of Fenofibrate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fenofibrate is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides, and Apo B, and to increase HDL-C adults with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate is also indicated to treat adults with severe hypertriglyceridemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A single 300mg oral dose of fenofibrate reaches a C max of 6-9.5mg/L with a T max of 4-6h in healthy, fasting volunteers. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fenofibrate is 0.89L/kg, and can be as high as 60L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fenofibrate is 99% protein bound in serum, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fenofibric acid, the active metabolite of fenofibrate, has a half life of 23 hours. Fenofibrate has a half life of 19-27 hours in healthy subjects and up to 143 hours in patients with renal failure. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance of fenofibrate is 1.1L/h in young adults and 1.2L/h in the elderly. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is >2g/kg and in mice is 1600mg/kg. The oral TDLO in rats is 9mg/kg. Treat patients with supportive care including monitoring of vital signs and observing clinical status. Recent overdose may be treated with inducing vomiting or gastric lavage. Due to fenofibrate's extensive protein binding, hemodialysis is not expected to be useful. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Antara, Cholib, Fenoglide, Fenomax, Lipidil Supra, Lipofen, Tricor, Triglide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fenofibrate Fenofibrato Fenofibratum Finofibrate Procetofen •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fenofibrate is a peroxisome proliferator receptor alpha activator used to lower LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C in hypercholesterolemia, dyslipidemia, and hypertriglyceridemia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Fentanyl interact?

•Drug A: Abatacept •Drug B: Fentanyl •Severity: MODERATE •Description: The metabolism of Fentanyl can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A7 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fentanyl intravenous or intramuscular injections are indicated for short term analgesia during induction, maintenance, and recovery from general or regional anesthesia. These injections are also used with a neuroleptic for premedication, induction, and as an adjunct to maintenance of anesthesia. Finally, fentanyl intravenous or intramuscular injections are used with oxygen for anesthesia in high risk patients. Fentanyl sublingual tablets, transmucosal lozenges, buccal tablets, sublingual sprays, transdermal systems, and nasal sprays are indicated for the management of breakthrough pain in opioid tolerant cancer patients who require around the clock pain management. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fentanyl produces strong analgesia through its activation of opioid receptors. It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids. Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fentanyl binds to opioid receptors, especially the mu opioid receptor, which are coupled to G-proteins. Activation of opioid receptors causes GTP to be exchanged for GDP on the G-proteins which in turn down regulates adenylate cyclase, reducing concentrations of cAMP. Reduced cAMP decreases cAMP dependant influx of calcium ions into the cell. The exchange of GTP for GDP results in hyperpolarization of the cell and inhibition of nerve activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fentanyl sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable). Fentanyl transmucosal lozenges reach a C max of 0.4±0.1ng/mL for a 200µg dose and 2.5±0.6ng/mL for a 1600µg dose with a T max of 20-40 minutes. The AUC was 172±96ng*min/mL for a 200µg dose and 1508±1360ng*min/mL for a 1600µg dose. Fentanyl sublingual spray reached a C max of 0.20±0.06ng/mL for a 100µg dose and 1.61±0.60ng/mL for an 800µg dose with a T max of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng*h/mL for a 100µg dose and 10.38±3.70ng*h/mL for a 800µg dose. Fentanyl transdermal systems reached a C max of 0.24±0.20ng/mL with a T max of 3.6±1.3h for a 25µg/h dose. The AUC was 0.42±0.35ng/mL*h. Fentanyl nasal spray reaches a C max of 815±301pg/mL with a T max of less than 1 hour for a 200µg/100µL dose. The AUC was 3772pg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The intravenous volume of distribution is 4L/kg (3-8L/kg). The oral volume of distribution is 25.4L/kg. In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8L/kg. Fentanyl crosses the blood brain barrier and the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fentanyl is 80-85% bound to plasma proteins. In one study, a 0.1µg/L solution of fentanyl was 77.9±1.1% bound to human serum albumin and 12.0±5.4% bound to α-1 acid glycoprotein. A 0.1µg/L solution of norfentanyl, the primary metabolite of fentanyl, was 7.62±1.2% bound to human serum albumin and 7.24±1.9% bound to α-1 acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fentanyl is metabolized to a number of inactive metabolites. Fentanyl is 99% N-dealkylated to norfentanyl by cytochrome P450. It can also be amide hydrolyzed to despropionylfentanyl, or alkyl hydroxylated to hydroxyfentanyl which is N-dealkylated to hydroxynorfentanyl. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with <7% unchanged, and 9% is excreted in the feces with <1% unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fentanyl is 7 hours. The half life of fentanyl sublingual spray is 5-12 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total plasma clearance of fentanyl is 0.5L/hr/kg (0.3-0.7L/hr/kg) or 42L/hr. Following an intravenous dose, surgical patients displayed a clearance of 27-75L/h, hepatically impaired patients displayed a clearance of 3-80L/h, and renally impaired patients displayed a clearance of 30-78L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fentanyl has an intravenous LD 50 of 2.91mg/kg in rats, an oral LD 50 of 18mg/kg in rats and 368mg/kg in mice. The LD50 in humans is not known. Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death. In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Abstral, Actiq, Duragesic, Effentora, Fentora, Instanyl, Lazanda, Sublimaze, Subsys •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fentanil Fentanila Fentanilo Fentanyl Fentanyl CII Fentanylum Phentanyl •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fentanyl is an opioid analgesic used in anesthesia, for breakthrough cancer pain, or round the clock pain management.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A7 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fentanyl interact? Information: •Drug A: Abatacept •Drug B: Fentanyl •Severity: MODERATE •Description: The metabolism of Fentanyl can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A7 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fentanyl intravenous or intramuscular injections are indicated for short term analgesia during induction, maintenance, and recovery from general or regional anesthesia. These injections are also used with a neuroleptic for premedication, induction, and as an adjunct to maintenance of anesthesia. Finally, fentanyl intravenous or intramuscular injections are used with oxygen for anesthesia in high risk patients. Fentanyl sublingual tablets, transmucosal lozenges, buccal tablets, sublingual sprays, transdermal systems, and nasal sprays are indicated for the management of breakthrough pain in opioid tolerant cancer patients who require around the clock pain management. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fentanyl produces strong analgesia through its activation of opioid receptors. It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids. Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fentanyl binds to opioid receptors, especially the mu opioid receptor, which are coupled to G-proteins. Activation of opioid receptors causes GTP to be exchanged for GDP on the G-proteins which in turn down regulates adenylate cyclase, reducing concentrations of cAMP. Reduced cAMP decreases cAMP dependant influx of calcium ions into the cell. The exchange of GTP for GDP results in hyperpolarization of the cell and inhibition of nerve activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fentanyl sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable). Fentanyl transmucosal lozenges reach a C max of 0.4±0.1ng/mL for a 200µg dose and 2.5±0.6ng/mL for a 1600µg dose with a T max of 20-40 minutes. The AUC was 172±96ng*min/mL for a 200µg dose and 1508±1360ng*min/mL for a 1600µg dose. Fentanyl sublingual spray reached a C max of 0.20±0.06ng/mL for a 100µg dose and 1.61±0.60ng/mL for an 800µg dose with a T max of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng*h/mL for a 100µg dose and 10.38±3.70ng*h/mL for a 800µg dose. Fentanyl transdermal systems reached a C max of 0.24±0.20ng/mL with a T max of 3.6±1.3h for a 25µg/h dose. The AUC was 0.42±0.35ng/mL*h. Fentanyl nasal spray reaches a C max of 815±301pg/mL with a T max of less than 1 hour for a 200µg/100µL dose. The AUC was 3772pg*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The intravenous volume of distribution is 4L/kg (3-8L/kg). The oral volume of distribution is 25.4L/kg. In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8L/kg. Fentanyl crosses the blood brain barrier and the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fentanyl is 80-85% bound to plasma proteins. In one study, a 0.1µg/L solution of fentanyl was 77.9±1.1% bound to human serum albumin and 12.0±5.4% bound to α-1 acid glycoprotein. A 0.1µg/L solution of norfentanyl, the primary metabolite of fentanyl, was 7.62±1.2% bound to human serum albumin and 7.24±1.9% bound to α-1 acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fentanyl is metabolized to a number of inactive metabolites. Fentanyl is 99% N-dealkylated to norfentanyl by cytochrome P450. It can also be amide hydrolyzed to despropionylfentanyl, or alkyl hydroxylated to hydroxyfentanyl which is N-dealkylated to hydroxynorfentanyl. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with <7% unchanged, and 9% is excreted in the feces with <1% unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fentanyl is 7 hours. The half life of fentanyl sublingual spray is 5-12 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total plasma clearance of fentanyl is 0.5L/hr/kg (0.3-0.7L/hr/kg) or 42L/hr. Following an intravenous dose, surgical patients displayed a clearance of 27-75L/h, hepatically impaired patients displayed a clearance of 3-80L/h, and renally impaired patients displayed a clearance of 30-78L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fentanyl has an intravenous LD 50 of 2.91mg/kg in rats, an oral LD 50 of 18mg/kg in rats and 368mg/kg in mice. The LD50 in humans is not known. Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death. In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Abstral, Actiq, Duragesic, Effentora, Fentora, Instanyl, Lazanda, Sublimaze, Subsys •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fentanil Fentanila Fentanilo Fentanyl Fentanyl CII Fentanylum Phentanyl •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fentanyl is an opioid analgesic used in anesthesia, for breakthrough cancer pain, or round the clock pain management. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A7 substrates. The severity of the interaction is moderate.

Does Abatacept and Fesoterodine interact?

•Drug A: Abatacept •Drug B: Fesoterodine •Severity: MODERATE •Description: The metabolism of Fesoterodine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fesoterodine is indicated for the treatment of overactive bladder in adult patients with symptoms of urge urinary incontinence, urgency, and frequency. It is also indicated in the treatment of neurogenic detrusor overactivity in pediatric patients ≥6 years old weighing >25 kg. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In-vivo the fesoteridine prodrug is broken down into its active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by plasma esterases. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. Therefore, acting as a competitive muscarinic receptor antagonist, fesoterodine ultimately acts to decrease the detrusor pressure by its muscarinic antagonism, thereby decreasing bladder contraction and consequently, the urge to urinate. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fesoterodine, once converted to its active metabolite, 5-hydroxymethyltolterodine, acts as a competitive antagonists at muscarinic receptors. This results in the inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Tmax (5-HMT): 5 hours post-adminitration of fesoterodine. AUC (0,∞)= 49.5 ng·h/ ml Bioavailability, 5-HMT = 52% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): IV, 5-HMT: 169 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 5-HMT: 50% to albumin and alpha1-acid glycoprotein •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized by ubiquitous, nonspecific esterases to transform fesoterodine into 5-HMT Extensive metabolism via CYP2D6 and CYP3A4 into inactive metabolites •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal: 70% of fesoterodine was recovered in urine as 5-HMT; 35% carboxy metabolite; 18% carboxy-N-desisopropylmetabolite, and 1% N-desisopropyl metabolite Fecal: 7% Hepatic: fesoterodine elimination via CYP2D6 and CYP3A4 •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7-8 hours for the active metabolite 5-hydroxymethyl tolterodine •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 5-HMT, healthy subjects: 14.4 L/h 5-HMT is also secreted into the nephron. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Rat, Oral, LD50: ~ 681 mg/kg Mouse, Oral, LD50: ~ 316 mg/kg Rat, Intravenous, NOAEL: 10 mg/kg Mouse, Intravenous, NOAEL: 10 mg/kg •Brand Names (Drug A): Orencia •Brand Names (Drug B): Toviaz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fesoterodine is an antimuscarinic agent used in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fesoterodine interact? Information: •Drug A: Abatacept •Drug B: Fesoterodine •Severity: MODERATE •Description: The metabolism of Fesoterodine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fesoterodine is indicated for the treatment of overactive bladder in adult patients with symptoms of urge urinary incontinence, urgency, and frequency. It is also indicated in the treatment of neurogenic detrusor overactivity in pediatric patients ≥6 years old weighing >25 kg. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In-vivo the fesoteridine prodrug is broken down into its active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by plasma esterases. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. Therefore, acting as a competitive muscarinic receptor antagonist, fesoterodine ultimately acts to decrease the detrusor pressure by its muscarinic antagonism, thereby decreasing bladder contraction and consequently, the urge to urinate. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fesoterodine, once converted to its active metabolite, 5-hydroxymethyltolterodine, acts as a competitive antagonists at muscarinic receptors. This results in the inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Tmax (5-HMT): 5 hours post-adminitration of fesoterodine. AUC (0,∞)= 49.5 ng·h/ ml Bioavailability, 5-HMT = 52% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): IV, 5-HMT: 169 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 5-HMT: 50% to albumin and alpha1-acid glycoprotein •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized by ubiquitous, nonspecific esterases to transform fesoterodine into 5-HMT Extensive metabolism via CYP2D6 and CYP3A4 into inactive metabolites •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal: 70% of fesoterodine was recovered in urine as 5-HMT; 35% carboxy metabolite; 18% carboxy-N-desisopropylmetabolite, and 1% N-desisopropyl metabolite Fecal: 7% Hepatic: fesoterodine elimination via CYP2D6 and CYP3A4 •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7-8 hours for the active metabolite 5-hydroxymethyl tolterodine •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 5-HMT, healthy subjects: 14.4 L/h 5-HMT is also secreted into the nephron. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Rat, Oral, LD50: ~ 681 mg/kg Mouse, Oral, LD50: ~ 316 mg/kg Rat, Intravenous, NOAEL: 10 mg/kg Mouse, Intravenous, NOAEL: 10 mg/kg •Brand Names (Drug A): Orencia •Brand Names (Drug B): Toviaz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fesoterodine is an antimuscarinic agent used in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Fexinidazole interact?

•Drug A: Abatacept •Drug B: Fexinidazole •Severity: MODERATE •Description: The metabolism of Fexinidazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fexinidazole is a nitroimidazole indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in patients 6 years of age and older weighing at least 20 kg. Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL), fexinidazole should only be used in these patients if there are no other available treatment options. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death. The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from in vitro studies was shown to be the minimum exposure time that was effectively trypanocidal. Although fexinidazole is effective in late-stage T. brucei gambiense HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with disulfiram itself; patients should avoid alcohol and disulfiram when taking fexinidazole. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal. Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range. Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox / eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection. The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean C max and AUC last increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled. Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the T max of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively. In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean C max for fexinidazole was 1.6 ± 0.4 μg/mL on day 1, 0.8 ± 0.3 μg/mL on day 2, and 0.5 ± 0.2 μg/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 μg/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 μg*h/mL. Concomitant food intake increases the C max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios. There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose. Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fexinidazole is an orally bioavailable 2-substituted 5-nitroimidazole used to treat early- and late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fexinidazole interact? Information: •Drug A: Abatacept •Drug B: Fexinidazole •Severity: MODERATE •Description: The metabolism of Fexinidazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fexinidazole is a nitroimidazole indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in patients 6 years of age and older weighing at least 20 kg. Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL), fexinidazole should only be used in these patients if there are no other available treatment options. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death. The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from in vitro studies was shown to be the minimum exposure time that was effectively trypanocidal. Although fexinidazole is effective in late-stage T. brucei gambiense HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with disulfiram itself; patients should avoid alcohol and disulfiram when taking fexinidazole. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal. Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range. Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox / eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection. The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean C max and AUC last increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled. Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the T max of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively. In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean C max for fexinidazole was 1.6 ± 0.4 μg/mL on day 1, 0.8 ± 0.3 μg/mL on day 2, and 0.5 ± 0.2 μg/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 μg/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 μg*h/mL. Concomitant food intake increases the C max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios. There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose. Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fexinidazole is an orally bioavailable 2-substituted 5-nitroimidazole used to treat early- and late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Fezolinetant interact?

•Drug A: Abatacept •Drug B: Fezolinetant •Severity: MODERATE •Description: The metabolism of Fezolinetant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fezolinetant has a high affinity for the NK3 receptor (K i value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity for NK1 or NK2 receptors. Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. A transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent. In a phase 2a clinical trial, fezolinetant 90 mg BID significantly reduce the frequency and severity of vasomotor symptoms in postmenopausal women by more than 50%. The improvement was observed as early as in the first week of treatment and was maintained throughout the 12 weeks of treatment. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In healthy women, fezolinetant C max and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once-daily doses, with minimal fezolinetant accumulation. The median (range) time to reach fezolinetant C max is 1.5 (1 to 4) hours in healthy women. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The effective half-life (t 1/2 ) of fezolinetant is 9.6 hours in women with vasomotor symptoms. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance at steady state of fezolinetant is 10.8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats. In the pre-and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36-fold the human AUC 24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC 24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC 24 at the human therapeutic dose). In the pre-and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC 24 at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC 24 at the human therapeutic dose). Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC 24 at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC 24 at the human therapeutic dose) showed reduced ovarian activity. Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m ) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m ). No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m ) or moderate (eGFR 30 to less than 60 mL/min/1.73 m ) renal impairment. Child-Pugh Class A or B hepatic impairment increased the exposure to fezolinetant. Fezolinetant has not been studied in individuals with Child-Pugh Class C hepatic impairment. In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC 24 at the human therapeutic dose of 45 mg, respectively. Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test. Treatment of overdose consists of discontinuation of fezolinetant therapy with the institution of appropriate symptomatic care. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Veozah •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fezolinetant is a non-hormonal drug used to treat moderate to severe vasomotor symptoms due to menopause.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fezolinetant interact? Information: •Drug A: Abatacept •Drug B: Fezolinetant •Severity: MODERATE •Description: The metabolism of Fezolinetant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fezolinetant has a high affinity for the NK3 receptor (K i value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity for NK1 or NK2 receptors. Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. A transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent. In a phase 2a clinical trial, fezolinetant 90 mg BID significantly reduce the frequency and severity of vasomotor symptoms in postmenopausal women by more than 50%. The improvement was observed as early as in the first week of treatment and was maintained throughout the 12 weeks of treatment. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In healthy women, fezolinetant C max and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once-daily doses, with minimal fezolinetant accumulation. The median (range) time to reach fezolinetant C max is 1.5 (1 to 4) hours in healthy women. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The effective half-life (t 1/2 ) of fezolinetant is 9.6 hours in women with vasomotor symptoms. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance at steady state of fezolinetant is 10.8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats. In the pre-and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36-fold the human AUC 24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC 24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC 24 at the human therapeutic dose). In the pre-and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC 24 at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC 24 at the human therapeutic dose). Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC 24 at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC 24 at the human therapeutic dose) showed reduced ovarian activity. Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m ) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m ). No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m ) or moderate (eGFR 30 to less than 60 mL/min/1.73 m ) renal impairment. Child-Pugh Class A or B hepatic impairment increased the exposure to fezolinetant. Fezolinetant has not been studied in individuals with Child-Pugh Class C hepatic impairment. In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC 24 at the human therapeutic dose of 45 mg, respectively. Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test. Treatment of overdose consists of discontinuation of fezolinetant therapy with the institution of appropriate symptomatic care. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Veozah •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fezolinetant is a non-hormonal drug used to treat moderate to severe vasomotor symptoms due to menopause. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Filgotinib interact?

•Drug A: Abatacept •Drug B: Filgotinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Filgotinib. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Filgotinib is indicated for the treatment of active moderate to severe rheumatoid arthritis alone or in combination with methotrexate. Filgotinib is currently reserved for patients who are unable to tolerate or who have not responded adequately to one or more disease-modifying anti-rheumatic drugs (DMARDS). Filgotinib is also indicated for treatment of moderately to severely active ulcerative colitis in adult patients who had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic agent. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In addition to targeted Janus kinase (JAK) 1 inhibition, filgotinib targets pro-inflammatory cytokine signalling by inhibiting IL-6 induced STAT1 phosphorylation. Serum C-reactive protein levels are also reduced in response to filgotinib administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There are four Janus kinase (JAK) enzymes including JAK1, JAK2, JAK3, and tyrosine kinase 2. JAK1 mediates inflammatory cytokine signaling, while JAK2 and JAK3 are important components of hematologic and immune functions. Filgotinib selectively inhibits JAK1 and is for example nearly 30-fold more selective for JAK1 compared to JAK2. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is implicated in several inflammatory pathologies and has been found to be continuously active in patients who have RA. Sustained activation of this pathway contributes to aberrant processes which lead to disease progression including elevated levels of matrix metalloproteinases (MMPs) and reduced cell apoptosis in RA affected synovial tissues. Filgotinib acts on the JAK-STAT pathway by selectively inhibiting JAK1 phosphorylation and preventing STAT activation, which ultimately results in reduced proinflammatory cytokine signaling. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Filgotinib is rapidly absorbed after oral administration. Median peak plasma concentrations occurred 2-3 hours post-dose for filgotinib and 5 hours post-dose for GS-829845. Steady-state concentrations can be observed in 2-3 days for filgotinib and in 4 days for GS-829845. Food does not appear to have a significant effect on the absorption of filgotinib; therefore, the medication can be administered without regard to food. After repeated oral dosing of filgotinib 200 mg, the reported Cmax and AUCτ values of filgotinib were 2.15 ug/mL and 6.77 ugxh/mL, respectively. For GS-829845 (the major metabolite) the reported Cmax was 4.43 ug/mL and the reported AUCτ was 83.2 ugxh/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 55-59% of filgotinib is protein-bound, while 39-44% of the active metabolite GS-829845 is protein-bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carboxylesterase enzymes are involved in the metabolism of filgotinib. The carboxylesterase 2 (CES2) isoform is chiefly responsible for metabolizing filgotinib to its major metabolite, GS-829845. Although carboxylesterase 1 (CES1) plays a less prominent role in the biotransformation of filgotinib, in vitro studies have demonstrated that CES1 will partially compensate in the event of CES2 saturation. GS-829845 is thus far the only major circulating metabolite to have been identified. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Of the total administered dose of filgotinib, approximately 87% undergoes renal elimination while 15% undergoes faecal elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of filgotinib is estimated to be 7 hours, while the half-life of its active metabolite GS-829845 is estimated to be 19 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding filgotinib is not readily available; however, it has been administered in clinical trials at doses of up to 450 mg daily. Associated adverse effects were similar to those observed at lower doses. In the event of overdose, the patient should be closely monitored and supportive measures should be initiated as required. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Filgotinib is a Janus kinase (JAK) 1 selective inhibitor used to treat cases of rheumatoid arthritis that are unresponsive to conventional treatments.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Filgotinib interact? Information: •Drug A: Abatacept •Drug B: Filgotinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Filgotinib. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Filgotinib is indicated for the treatment of active moderate to severe rheumatoid arthritis alone or in combination with methotrexate. Filgotinib is currently reserved for patients who are unable to tolerate or who have not responded adequately to one or more disease-modifying anti-rheumatic drugs (DMARDS). Filgotinib is also indicated for treatment of moderately to severely active ulcerative colitis in adult patients who had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic agent. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In addition to targeted Janus kinase (JAK) 1 inhibition, filgotinib targets pro-inflammatory cytokine signalling by inhibiting IL-6 induced STAT1 phosphorylation. Serum C-reactive protein levels are also reduced in response to filgotinib administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There are four Janus kinase (JAK) enzymes including JAK1, JAK2, JAK3, and tyrosine kinase 2. JAK1 mediates inflammatory cytokine signaling, while JAK2 and JAK3 are important components of hematologic and immune functions. Filgotinib selectively inhibits JAK1 and is for example nearly 30-fold more selective for JAK1 compared to JAK2. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is implicated in several inflammatory pathologies and has been found to be continuously active in patients who have RA. Sustained activation of this pathway contributes to aberrant processes which lead to disease progression including elevated levels of matrix metalloproteinases (MMPs) and reduced cell apoptosis in RA affected synovial tissues. Filgotinib acts on the JAK-STAT pathway by selectively inhibiting JAK1 phosphorylation and preventing STAT activation, which ultimately results in reduced proinflammatory cytokine signaling. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Filgotinib is rapidly absorbed after oral administration. Median peak plasma concentrations occurred 2-3 hours post-dose for filgotinib and 5 hours post-dose for GS-829845. Steady-state concentrations can be observed in 2-3 days for filgotinib and in 4 days for GS-829845. Food does not appear to have a significant effect on the absorption of filgotinib; therefore, the medication can be administered without regard to food. After repeated oral dosing of filgotinib 200 mg, the reported Cmax and AUCτ values of filgotinib were 2.15 ug/mL and 6.77 ugxh/mL, respectively. For GS-829845 (the major metabolite) the reported Cmax was 4.43 ug/mL and the reported AUCτ was 83.2 ugxh/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 55-59% of filgotinib is protein-bound, while 39-44% of the active metabolite GS-829845 is protein-bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carboxylesterase enzymes are involved in the metabolism of filgotinib. The carboxylesterase 2 (CES2) isoform is chiefly responsible for metabolizing filgotinib to its major metabolite, GS-829845. Although carboxylesterase 1 (CES1) plays a less prominent role in the biotransformation of filgotinib, in vitro studies have demonstrated that CES1 will partially compensate in the event of CES2 saturation. GS-829845 is thus far the only major circulating metabolite to have been identified. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Of the total administered dose of filgotinib, approximately 87% undergoes renal elimination while 15% undergoes faecal elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of filgotinib is estimated to be 7 hours, while the half-life of its active metabolite GS-829845 is estimated to be 19 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding filgotinib is not readily available; however, it has been administered in clinical trials at doses of up to 450 mg daily. Associated adverse effects were similar to those observed at lower doses. In the event of overdose, the patient should be closely monitored and supportive measures should be initiated as required. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Filgotinib is a Janus kinase (JAK) 1 selective inhibitor used to treat cases of rheumatoid arthritis that are unresponsive to conventional treatments. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Finasteride interact?

•Drug A: Abatacept •Drug B: Finasteride •Severity: MODERATE •Description: The metabolism of Finasteride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Finasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. A combination product with tadalafil is also used for the symptomatic treatment of BPH for up to 26 weeks. Finasteride is also indicated for the treatment of male pattern hair loss (androgenetic alopecia, hereditary alopecia, or common male baldness) in male patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Finasteride is an antiandrogenic compound that works by suppressing the production of serum and intraprostatic dihydrotestosterone (DHT) in men via inhibiting the enzyme responsible for the biosynthesis of DHT. The maximum effect of a rapid reduction in serum DHT concentration is expected to be observed 8 hours following administration of the first dose. In a single man receiving a single oral dose of 5 mg finasteride for up to 4 years, there was a reduction in the serum DHT concentrations by approximately 70% and the median circulating level of testosterone increased by approximately 10-20% within the physiologic range. In a double-blind, placebo-controlled study, finasteride reduced intraprostatic DHT level by 91.4% but finasteride is not expected to decrease the DHT levels to castrate levels since circulating testosterone is also converted to DHT by the type 1 isoenzyme expressed in other tissues. It is expected that DHT levels return to normal within 14 days upon discontinuation of the drug. In a study of male patients with benign prostatic hyperplasia prior to prostatectomy, the treatment with finasteride resulted in an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery compared to placebo. While finasteride reduces the size of the prostate gland by 20%, this may not correlate well with improvement in symptoms. The effects of finasteride are reported to be more pronounced in male patients with enlarged prostates (>25 mL) who are at the greatest risk of disease progression. In phase III clinical studies, oral administration of finasteride in male patients with male pattern hair loss promoted hair growth and prevented further hair loss by 66% and 83% of the subjects, respectively, which lasted during two years' treatment. The incidences of these effects in treatment groups were significantly higher than that of the group receiving a placebo. Following finasteride administration, the levels of DHT in the scalp skin was shown to be reduced by more than 60%, indicating that the DHT found in scalp is derived from both local DHT production and circulating DHT. The effect of finasteride on scalp DHT is likely seen because of its effect on both local follicular DHT levels as well as serum DHT levels.. There is evidence from early clinical observations and controlled studies that finasteride may reduce bleeding of prostatic origin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Finasteride acts as a competitive and specific inhibitor of Type II 5α-reductase, a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the development and enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the production of DHT together with type I 5α-reductase, the type II 5α-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver. Although finasteride is 100-fold more selective for type II 5α-reductase than for the type I isoenzyme, chronic treatment with this drug may have some effect on type I 5α-reductase, which is predominantly expressed in sebaceous glands of most regions of skin, including the scalp, and liver. It is proposed that the type I 5α-reductase and type II 5α-reductase is responsible for the production of one-third and two-thirds of circulating DHT, respectively. The mechanism of action of Finasteride is based on its preferential inhibition of Type II 5α-reductase through the formation of a stable complex with the enzyme in vitro and in vivo. Finasteride works selectively, where it preferentially displays a 100-fold selectivity for the human Type II 5α-reductase over type I enzyme. Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant decreases in serum and tissue DHT concentrations, minimal to moderate increase in serum testosterone concentrations, and substantial increases in prostatic testosterone concentrations. As DHT appears to be the principal androgen responsible for stimulation of prostatic growth, a decrease in DHT concentrations will result in a decrease in prostatic volume (approximately 20-30% after 6-24 months of continued therapy). It is suggested that increased levels of DHT can lead to potentiated transcription of prostaglandin D2, which promotes the proliferation of prostate cancer cells. In men with androgenic alopecia, the mechanism of action has not been fully determined, but finasteride has shown to decrease scalp DHT concentration to the levels found in the hairy scalp, reduce serum DHT, increase hair regrowth, and slow hair loss. Another study suggests that finasteride may work to reduce bleeding of prostatic origin by inhibiting vascular endothelial growth factor (VEGF) in the prostate, leading to atrophy and programmed cell death. This may bestow the drug therapeutic benefits in patients idiopathic prostatic bleeding, bleeding during anticoagulation, or bleeding after instrumentation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Finasteride is well absorbed following oral administration and displays a slow accumulation phase after multiple dosing.[lablel] In healthy male subjects receiving oral finasteride, the mean oral bioavailability was 65% for 1 mg finasteride and 63% for 5 mg finasteride, and the values ranged from 26 to 170% for 1 mg dose and from 34 to 108% for 5 mg dose, respectively. It is reported that food intake does not affect the oral bioavailability of the drug. The peak plasma concentrations (Cmax) averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2 hours post administration. The AUC(0-24 hr) was 53 ngxhr/mL (range, 20-154 ngxhr/mL). The plasma concentrations and AUC are reported to be higher in elderly male patients aged 70 years or older. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution is 76 L at steady state, ranging from 44 to 96 L. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. It is not known whether finasteride is excreted in human milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 90% of circulating finasteride is bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Finasteride undergoes extensive hepatic metabolism predominantly mediated by the cytochrome P450 3A4 (CYP3A4) enzyme to form the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites. Theses metabolites retain less than 20% of the pharmacological activity of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In healthy subjects, about 32-46% of total oral dose of finasteride was excreted in the urine in the form of metabolites while about 51-64% of the dose was excreted in the feces. In patients with renal impairment, the extent of urinary excretion of finasteride is expected to be decreased while the fecal excretion is increased. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy young subjects receiving finasteride, the mean elimination half-life in plasma was 6 hours ranging from 3 to 16 hours. In elderly patients over the age of 70 years, the half-life is prolonged to 8 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy young subjects (n=15), the mean plasma clearance of finasteride was 165 mL/min with the range between 70 and 279 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 Oral LD50 is about 418 mg/kg in rats and there have been cases of lethality in rats receiving a single oral dose of 400 mg/kg in males and 1000 mg/kg in females. Nonclinical toxicology In a 24-month rat study, there were no signs of the tumorigenic potential of finasteride. In a 19-month carcinogenicity study in CD-1 mice, high doses of finasteride, at 1824 times the human exposure (250 mg/kg/day), resulted in an increase in the incidence of testicular Leydig cell adenomas and an increase in serum LH levels. In vitro mutagenesis assays demonstrated no evidence of mutagenicity. In an in vitro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations with much higher doses of finasteride. Overdose There were no reported significant adverse events in clinical trials of male patients receiving single oral doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months. As there have been no cases of overdose or clinically significant toxicity with finasteride, there are no specific recommendations in case of an overdose. Significant adverse events Common reproductive adverse events seen with finasteride therapy include erectile dysfunction, ejaculatory dysfunction, and loss of libido. These adverse events tend to disappear after discontinuation or chronic use of the drug. Only causal adverse event occurring at the male reproductive system that is caused by finasteride is decreased ejaculatory volume because of the predominant action of DHT on the prostate. Special populations Finasteride can be safely used in elderly patients or those with renal impairment with no specific dosing adjustment recommendations. Finasteride is indicated for male patients only, and it is advised that exposure to finasteride is avoided in pregnant women carrying male fetuses as it may lead to abnormal development of external genitalia in male fetuses. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Entadfi, Propecia, Proscar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Finasterida Finasteride Finasteridum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Finasteride is an antiandrogenic compound that is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) and male pattern hair loss in adult males by inhibiting Type II 5-alpha reductase.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Finasteride interact? Information: •Drug A: Abatacept •Drug B: Finasteride •Severity: MODERATE •Description: The metabolism of Finasteride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Finasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. A combination product with tadalafil is also used for the symptomatic treatment of BPH for up to 26 weeks. Finasteride is also indicated for the treatment of male pattern hair loss (androgenetic alopecia, hereditary alopecia, or common male baldness) in male patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Finasteride is an antiandrogenic compound that works by suppressing the production of serum and intraprostatic dihydrotestosterone (DHT) in men via inhibiting the enzyme responsible for the biosynthesis of DHT. The maximum effect of a rapid reduction in serum DHT concentration is expected to be observed 8 hours following administration of the first dose. In a single man receiving a single oral dose of 5 mg finasteride for up to 4 years, there was a reduction in the serum DHT concentrations by approximately 70% and the median circulating level of testosterone increased by approximately 10-20% within the physiologic range. In a double-blind, placebo-controlled study, finasteride reduced intraprostatic DHT level by 91.4% but finasteride is not expected to decrease the DHT levels to castrate levels since circulating testosterone is also converted to DHT by the type 1 isoenzyme expressed in other tissues. It is expected that DHT levels return to normal within 14 days upon discontinuation of the drug. In a study of male patients with benign prostatic hyperplasia prior to prostatectomy, the treatment with finasteride resulted in an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery compared to placebo. While finasteride reduces the size of the prostate gland by 20%, this may not correlate well with improvement in symptoms. The effects of finasteride are reported to be more pronounced in male patients with enlarged prostates (>25 mL) who are at the greatest risk of disease progression. In phase III clinical studies, oral administration of finasteride in male patients with male pattern hair loss promoted hair growth and prevented further hair loss by 66% and 83% of the subjects, respectively, which lasted during two years' treatment. The incidences of these effects in treatment groups were significantly higher than that of the group receiving a placebo. Following finasteride administration, the levels of DHT in the scalp skin was shown to be reduced by more than 60%, indicating that the DHT found in scalp is derived from both local DHT production and circulating DHT. The effect of finasteride on scalp DHT is likely seen because of its effect on both local follicular DHT levels as well as serum DHT levels.. There is evidence from early clinical observations and controlled studies that finasteride may reduce bleeding of prostatic origin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Finasteride acts as a competitive and specific inhibitor of Type II 5α-reductase, a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the development and enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the production of DHT together with type I 5α-reductase, the type II 5α-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver. Although finasteride is 100-fold more selective for type II 5α-reductase than for the type I isoenzyme, chronic treatment with this drug may have some effect on type I 5α-reductase, which is predominantly expressed in sebaceous glands of most regions of skin, including the scalp, and liver. It is proposed that the type I 5α-reductase and type II 5α-reductase is responsible for the production of one-third and two-thirds of circulating DHT, respectively. The mechanism of action of Finasteride is based on its preferential inhibition of Type II 5α-reductase through the formation of a stable complex with the enzyme in vitro and in vivo. Finasteride works selectively, where it preferentially displays a 100-fold selectivity for the human Type II 5α-reductase over type I enzyme. Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant decreases in serum and tissue DHT concentrations, minimal to moderate increase in serum testosterone concentrations, and substantial increases in prostatic testosterone concentrations. As DHT appears to be the principal androgen responsible for stimulation of prostatic growth, a decrease in DHT concentrations will result in a decrease in prostatic volume (approximately 20-30% after 6-24 months of continued therapy). It is suggested that increased levels of DHT can lead to potentiated transcription of prostaglandin D2, which promotes the proliferation of prostate cancer cells. In men with androgenic alopecia, the mechanism of action has not been fully determined, but finasteride has shown to decrease scalp DHT concentration to the levels found in the hairy scalp, reduce serum DHT, increase hair regrowth, and slow hair loss. Another study suggests that finasteride may work to reduce bleeding of prostatic origin by inhibiting vascular endothelial growth factor (VEGF) in the prostate, leading to atrophy and programmed cell death. This may bestow the drug therapeutic benefits in patients idiopathic prostatic bleeding, bleeding during anticoagulation, or bleeding after instrumentation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Finasteride is well absorbed following oral administration and displays a slow accumulation phase after multiple dosing.[lablel] In healthy male subjects receiving oral finasteride, the mean oral bioavailability was 65% for 1 mg finasteride and 63% for 5 mg finasteride, and the values ranged from 26 to 170% for 1 mg dose and from 34 to 108% for 5 mg dose, respectively. It is reported that food intake does not affect the oral bioavailability of the drug. The peak plasma concentrations (Cmax) averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2 hours post administration. The AUC(0-24 hr) was 53 ngxhr/mL (range, 20-154 ngxhr/mL). The plasma concentrations and AUC are reported to be higher in elderly male patients aged 70 years or older. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution is 76 L at steady state, ranging from 44 to 96 L. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. It is not known whether finasteride is excreted in human milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 90% of circulating finasteride is bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Finasteride undergoes extensive hepatic metabolism predominantly mediated by the cytochrome P450 3A4 (CYP3A4) enzyme to form the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites. Theses metabolites retain less than 20% of the pharmacological activity of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In healthy subjects, about 32-46% of total oral dose of finasteride was excreted in the urine in the form of metabolites while about 51-64% of the dose was excreted in the feces. In patients with renal impairment, the extent of urinary excretion of finasteride is expected to be decreased while the fecal excretion is increased. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy young subjects receiving finasteride, the mean elimination half-life in plasma was 6 hours ranging from 3 to 16 hours. In elderly patients over the age of 70 years, the half-life is prolonged to 8 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy young subjects (n=15), the mean plasma clearance of finasteride was 165 mL/min with the range between 70 and 279 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 Oral LD50 is about 418 mg/kg in rats and there have been cases of lethality in rats receiving a single oral dose of 400 mg/kg in males and 1000 mg/kg in females. Nonclinical toxicology In a 24-month rat study, there were no signs of the tumorigenic potential of finasteride. In a 19-month carcinogenicity study in CD-1 mice, high doses of finasteride, at 1824 times the human exposure (250 mg/kg/day), resulted in an increase in the incidence of testicular Leydig cell adenomas and an increase in serum LH levels. In vitro mutagenesis assays demonstrated no evidence of mutagenicity. In an in vitro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations with much higher doses of finasteride. Overdose There were no reported significant adverse events in clinical trials of male patients receiving single oral doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months. As there have been no cases of overdose or clinically significant toxicity with finasteride, there are no specific recommendations in case of an overdose. Significant adverse events Common reproductive adverse events seen with finasteride therapy include erectile dysfunction, ejaculatory dysfunction, and loss of libido. These adverse events tend to disappear after discontinuation or chronic use of the drug. Only causal adverse event occurring at the male reproductive system that is caused by finasteride is decreased ejaculatory volume because of the predominant action of DHT on the prostate. Special populations Finasteride can be safely used in elderly patients or those with renal impairment with no specific dosing adjustment recommendations. Finasteride is indicated for male patients only, and it is advised that exposure to finasteride is avoided in pregnant women carrying male fetuses as it may lead to abnormal development of external genitalia in male fetuses. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Entadfi, Propecia, Proscar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Finasterida Finasteride Finasteridum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Finasteride is an antiandrogenic compound that is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) and male pattern hair loss in adult males by inhibiting Type II 5-alpha reductase. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Finerenone interact?

•Drug A: Abatacept •Drug B: Finerenone •Severity: MODERATE •Description: The metabolism of Finerenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the US, finerenone is indicated to reduce the risk of sustained decline in glomerular filtration rate, end stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with chronic kidney disease associated with type II diabetes mellitus. In Europe, finerenone is indicated for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Finerenone is a non-steroidal mineralocorticoid receptor antagonist indicated to reduce the risk of sustained decline in glomerular filtration rate, end stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with chronic kidney disease associated with type II diabetes mellitus. It has a moderate duration of action as it is taken once daily, and a wide therapeutic window as patients were given doses from 1.25 mg to 80 mg in clinical trials. Patients should be counselled regarding the risk of hyperkalemia. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Finerenone is a non-steroidal selective mineralocorticoid receptor (MR) antagonist with no significant affinity or activity at androgen, progesterone, estrogen, and glucocorticoid receptors. Animal studies have shown that finerenone binding to the MR reduces inflammation and fibrosis, and phase 2 clinical trials showed a reduction in albuminuria. Aldosterone is a mineralocorticoid hormone involved in the regulation of blood pressure, sodium reabsorption, and potassium excretion. In 1943, agonism of the MR along with increased salt was shown to be associated with malignant hypertension, which could progress to inflammation and fibrosis of organs. Binding of aldosterone, an MR agonist, to the MR causes a conformational change, which dissociates the receptor from inactivating chaperone proteins. The active MR translocates to the nucleus along with a complex of other coactivators to induce transcription of a number of genes. Finerenone's binding to the MR prevents binding of MR coactivators, which in turn prevents pro-inflammatory and pro-fibrotic gene transcription. Clinical trial data shows that blocking the mineralocorticoid receptor reduces mortality and morbidity in patients with chronic severe congestive heart failure with an ejection fraction ≤35%. Patients taking finerenone developed new onset atrial fibrillation or flutter (AFF) with a hazard ratio of 0.71. Finerenone lowered the risk of first onset of kidney failure, a sustained eGFR decrease of ≥40%, or death from a renal cause to a hazard ratio of 0.82. Cardiovascular outcomes including cardiovascular death, nonfatal heart attacks, nonfatal strokes, and hospitalization for heart failure in patients taking finerenone had a hazard ratio of 0.86 in patients with a history of AFF and 0.85 in patients without a history of AFF. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 10 mg oral dose of finerenone reaches a C max of 351 µg/L, with a T max of 1.5 hours, and an AUC of 2820 µg*h/L in plasma. The same dose of finerenone reaches a C max of 226 µg/L, with a T max of 1.5 hours, and an AUC of 1840 µg*h/L in whole blood. Regular doses of 20 mg of finerenone reach a geometric mean steady state C max of 160 µg/L with an AUC of 686 µg*h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of finerenone as steady state is 52.6L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Finerenone is 92% protein bound in plasma; predominantly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Finerenone is approximately 90% metabolized by CYP3A4, and 10% metabolized by CYP2C8. There is a minor contribution to metabolism by CYP1A1. Finerenone has no active metabolites. Finerenone is aromatized to the M1 metabolite by CYP3A4 and CYP2C8, which is further hydroxylated by CYP3A4 to the M2 metabolite, and finally oxidized bye CYP3A4 to the M3 metabolite. Alternatively, finerenone can undergo epoxidation and possibly hydrolysis by CYP3A4 and CYP2C8 to form the M4 metabolite, which is hydroxylated again by CYP3A4 to the M5 metabolite, and oxidized to the M8 metabolite. Finerenone can also be hydroxylated by CYP2C8 to the M7 metabolite, and further oxidized to the M9 metabolite. The M10 metabolite is formed by the demethylation, oxidation, and ring opening of finerenone. The M13 metabolite is formed through de-ethylation of finerenone by CYP1A1, and the M14 metabolite is formed through an undefined multi-step process involving CYP2C8 and CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The majority of the dose recovered in urine was in the form of the M2, M3 (47.8%), and M4 metabolites; <1.3% of the dose recovered in the urine was as the unchanged parent compound. The majority of the dose recovered in the feces was as the M5 metabolite, with only 0.2% eliminated as the unchanged parent compound. The M1 metabolite made up <1.5% of the recovered dose in urine and feces. Finerenone is not expected to be metabolized by the intestinal microflora. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of a 10 mg dose of finerenone in 4 healthy men was 17.4 hours in plasma and 12.3 hours in whole blood. The terminal half life of finerenone is approximately 2-3 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The systemic clearance of finerenone is approximately 25 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose of finerenone may experience hyperkalemia. In the even of an overdose, immediately stop taking finerenone. Treat patients with symptomatic and supportive treatment, including treatment for hyperkalemia if it develops. Hemodialysis is not expected to remove finerenone from the blood due to its high plasma protein binding. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kerendia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Finerenone is a nonsteroidal mineralocorticoid receptor antagonist indicated to lower the risk of eGFR decline, end stage kidney disease, cardiovascular death, heart attack, and hospitalization for heart failure in chronic kidney disease associated with type 2 diabetes.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Finerenone interact? Information: •Drug A: Abatacept •Drug B: Finerenone •Severity: MODERATE •Description: The metabolism of Finerenone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the US, finerenone is indicated to reduce the risk of sustained decline in glomerular filtration rate, end stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with chronic kidney disease associated with type II diabetes mellitus. In Europe, finerenone is indicated for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Finerenone is a non-steroidal mineralocorticoid receptor antagonist indicated to reduce the risk of sustained decline in glomerular filtration rate, end stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with chronic kidney disease associated with type II diabetes mellitus. It has a moderate duration of action as it is taken once daily, and a wide therapeutic window as patients were given doses from 1.25 mg to 80 mg in clinical trials. Patients should be counselled regarding the risk of hyperkalemia. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Finerenone is a non-steroidal selective mineralocorticoid receptor (MR) antagonist with no significant affinity or activity at androgen, progesterone, estrogen, and glucocorticoid receptors. Animal studies have shown that finerenone binding to the MR reduces inflammation and fibrosis, and phase 2 clinical trials showed a reduction in albuminuria. Aldosterone is a mineralocorticoid hormone involved in the regulation of blood pressure, sodium reabsorption, and potassium excretion. In 1943, agonism of the MR along with increased salt was shown to be associated with malignant hypertension, which could progress to inflammation and fibrosis of organs. Binding of aldosterone, an MR agonist, to the MR causes a conformational change, which dissociates the receptor from inactivating chaperone proteins. The active MR translocates to the nucleus along with a complex of other coactivators to induce transcription of a number of genes. Finerenone's binding to the MR prevents binding of MR coactivators, which in turn prevents pro-inflammatory and pro-fibrotic gene transcription. Clinical trial data shows that blocking the mineralocorticoid receptor reduces mortality and morbidity in patients with chronic severe congestive heart failure with an ejection fraction ≤35%. Patients taking finerenone developed new onset atrial fibrillation or flutter (AFF) with a hazard ratio of 0.71. Finerenone lowered the risk of first onset of kidney failure, a sustained eGFR decrease of ≥40%, or death from a renal cause to a hazard ratio of 0.82. Cardiovascular outcomes including cardiovascular death, nonfatal heart attacks, nonfatal strokes, and hospitalization for heart failure in patients taking finerenone had a hazard ratio of 0.86 in patients with a history of AFF and 0.85 in patients without a history of AFF. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): A 10 mg oral dose of finerenone reaches a C max of 351 µg/L, with a T max of 1.5 hours, and an AUC of 2820 µg*h/L in plasma. The same dose of finerenone reaches a C max of 226 µg/L, with a T max of 1.5 hours, and an AUC of 1840 µg*h/L in whole blood. Regular doses of 20 mg of finerenone reach a geometric mean steady state C max of 160 µg/L with an AUC of 686 µg*h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of finerenone as steady state is 52.6L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Finerenone is 92% protein bound in plasma; predominantly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Finerenone is approximately 90% metabolized by CYP3A4, and 10% metabolized by CYP2C8. There is a minor contribution to metabolism by CYP1A1. Finerenone has no active metabolites. Finerenone is aromatized to the M1 metabolite by CYP3A4 and CYP2C8, which is further hydroxylated by CYP3A4 to the M2 metabolite, and finally oxidized bye CYP3A4 to the M3 metabolite. Alternatively, finerenone can undergo epoxidation and possibly hydrolysis by CYP3A4 and CYP2C8 to form the M4 metabolite, which is hydroxylated again by CYP3A4 to the M5 metabolite, and oxidized to the M8 metabolite. Finerenone can also be hydroxylated by CYP2C8 to the M7 metabolite, and further oxidized to the M9 metabolite. The M10 metabolite is formed by the demethylation, oxidation, and ring opening of finerenone. The M13 metabolite is formed through de-ethylation of finerenone by CYP1A1, and the M14 metabolite is formed through an undefined multi-step process involving CYP2C8 and CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The majority of the dose recovered in urine was in the form of the M2, M3 (47.8%), and M4 metabolites; <1.3% of the dose recovered in the urine was as the unchanged parent compound. The majority of the dose recovered in the feces was as the M5 metabolite, with only 0.2% eliminated as the unchanged parent compound. The M1 metabolite made up <1.5% of the recovered dose in urine and feces. Finerenone is not expected to be metabolized by the intestinal microflora. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of a 10 mg dose of finerenone in 4 healthy men was 17.4 hours in plasma and 12.3 hours in whole blood. The terminal half life of finerenone is approximately 2-3 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The systemic clearance of finerenone is approximately 25 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose of finerenone may experience hyperkalemia. In the even of an overdose, immediately stop taking finerenone. Treat patients with symptomatic and supportive treatment, including treatment for hyperkalemia if it develops. Hemodialysis is not expected to remove finerenone from the blood due to its high plasma protein binding. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kerendia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Finerenone is a nonsteroidal mineralocorticoid receptor antagonist indicated to lower the risk of eGFR decline, end stage kidney disease, cardiovascular death, heart attack, and hospitalization for heart failure in chronic kidney disease associated with type 2 diabetes. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Does Abatacept and Fingolimod interact?

•Drug A: Abatacept •Drug B: Fingolimod •Severity: MODERATE •Description: Abatacept may increase the immunosuppressive activities of Fingolimod. •Extended Description: When administered concurrently with fingolimod, immunosuppressive agents may exert an additive immunosuppressive effect. As a result, there is a greater risk of infection. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation. In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease. Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous systems. S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system. The active form of the drug, fingolimod phosphate, is a sphingosine 1-phosphate receptor modulator that exerts its mechanism of action in MS by binding to various sphingosine 1-phosphate receptors (1, 3, 4, and 5). It suppresses the exit of lymphocytes from lymph nodes, leading to a lower level of lymphocytes circulating in the peripheral circulation. This reduces the inflammation that is associated with MS. The mechanism of action of fingolimod is not fully understood but may be related to reduced lymphocyte circulation into the central nervous system. Immune modulating treatment such as fingolimod is not typically employed for SARS-CoV-2 pneumonia. Despite this, with the tissue findings of pulmonary edema and hyaline membrane formation, the timely use of immune modulators such as fingolimod can be considered to prevent acute respiratory distress syndrome (ARDS) associated with COVID-19. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod. The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of fingolimod and its active metabolite exceeds 99.7%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites. Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of fingolimod and its active metabolite ranges from 6-9 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fingolimod blood clearance is 6.3±2.3 L/h, according to prescribing information. Another resource mentions it ranges from 6-8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The LD50 of fingolimod in rats ranges from 300-600 mg/kg. Prescribing information for fingolimod does not mention symptoms or management of an overdose, however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine. Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gilenya, Tascenso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fingolimod is a sphingosine 1-phosphate receptor modulator used to treat patients with the relapsing-remitting form of multiple sclerosis (MS) and studied to manage lung complications of COVID-19.

When administered concurrently with fingolimod, immunosuppressive agents may exert an additive immunosuppressive effect. As a result, there is a greater risk of infection. The severity of the interaction is moderate.

Question: Does Abatacept and Fingolimod interact? Information: •Drug A: Abatacept •Drug B: Fingolimod •Severity: MODERATE •Description: Abatacept may increase the immunosuppressive activities of Fingolimod. •Extended Description: When administered concurrently with fingolimod, immunosuppressive agents may exert an additive immunosuppressive effect. As a result, there is a greater risk of infection. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation. In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease. Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous systems. S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system. The active form of the drug, fingolimod phosphate, is a sphingosine 1-phosphate receptor modulator that exerts its mechanism of action in MS by binding to various sphingosine 1-phosphate receptors (1, 3, 4, and 5). It suppresses the exit of lymphocytes from lymph nodes, leading to a lower level of lymphocytes circulating in the peripheral circulation. This reduces the inflammation that is associated with MS. The mechanism of action of fingolimod is not fully understood but may be related to reduced lymphocyte circulation into the central nervous system. Immune modulating treatment such as fingolimod is not typically employed for SARS-CoV-2 pneumonia. Despite this, with the tissue findings of pulmonary edema and hyaline membrane formation, the timely use of immune modulators such as fingolimod can be considered to prevent acute respiratory distress syndrome (ARDS) associated with COVID-19. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod. The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of fingolimod and its active metabolite exceeds 99.7%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites. Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of fingolimod and its active metabolite ranges from 6-9 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Fingolimod blood clearance is 6.3±2.3 L/h, according to prescribing information. Another resource mentions it ranges from 6-8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The LD50 of fingolimod in rats ranges from 300-600 mg/kg. Prescribing information for fingolimod does not mention symptoms or management of an overdose, however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine. Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gilenya, Tascenso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fingolimod is a sphingosine 1-phosphate receptor modulator used to treat patients with the relapsing-remitting form of multiple sclerosis (MS) and studied to manage lung complications of COVID-19. Output: When administered concurrently with fingolimod, immunosuppressive agents may exert an additive immunosuppressive effect. As a result, there is a greater risk of infection. The severity of the interaction is moderate.

Does Abatacept and Flecainide interact?

•Drug A: Abatacept •Drug B: Flecainide •Severity: MAJOR •Description: The metabolism of Flecainide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In New Zealand and America, flecainide is indicated to prevent supraventricular arrhythmias and ventricular arrhythmias. In the United States, it is also indicated to prevent paroxysmal atrial fibrillation and flutter. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flecainide inhibits the action of sodium and potassium ion channels in the heart, raising the threshold for depolarization and correcting arrhythmias. Flecainide has a long duration of action, allowing for once daily dosing. The therapeutic index is narrow. Patients should not take this medication if there is already structural heart disease or left ventricular systolic dysfunction. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flecainide blocks fast inward sodium channels and slowly unbinds during diastole, prolonging the refractory period of the heart. This blockade also shortens the duration of action potentials through the Purkinjie fibers. Flecainide also prevents delayed rectifier potassium channels from opening, lengthening the action potential through ventricular and atrial muscle fibers. Finally, flecainide also blocks ryanodine receptor opening, reducing calcium release from sarcoplasmic reticulum, which reduces depolarization of cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral flecainide has a T max of 3-4h and a bioavialability of 90%. Taking flecainide with food or aluminum hydroxide antacids do not significantly affect the absorption of flecainide. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average volume of distribution in 8 male subjects is 5.0-13.4L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Flecainide is 40% bound to protein in serum, mainly to alpha-1-acid glycoprotein and minorly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flecainide is mainly metabolized to meta-O-dealkylated flecainide or the meta-O-dealkylated lactam of flecainide. Meta-O-dealkylated flecainide has 20% the activity of flecainide. Both of these metabolites are generally detected as glucuronide or sulfate conjugates. Flecainide’s metabolism involves the action of CYP2D6 and CYP1A2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 86% of a single oral dose is eliminated in the urine, with 42% as unchanged flecainide and 14% as meta-O-dealkylated flecainide, a similar amount of the meta-O-dealkylated lactam of flecainide, approximately 3% as an unidentified acid metabolite, and <1% as 2 other unknown metabolites. 5% is eliminated in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy subjects, intravenous flecainide has an average half life of 13 hours for a single dose and 16 hours for multiple oral doses. In patients with a ventricular premature complex, flecainide has a half life of 20 hours. The half life of meta-O-dealkylated flecainide, a major metabolite of flecainide, is 12.6h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance of intravenous flecainide is 4.6-12.1mL/min/kg in 8 male subjects. For oral flecainide, the clearance was 4-20mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 1346mg/kg and in mice is 170mg/kg. The subcutaneous LD 50 in rats is 215mg/kg and in mice is 188mg/kg. The oral TDLO in women is 20mg/kg and in men is 40mg/kg/2W. Patients experiencing an overdose may present with ECG abnormalities such as a lengthened PR interval, increased QRS duration, prolonged QT interval, increased amplitude of the T wave, reduced myocardial rate and contractility, hypotension, or death. Treat patients with symptomatic and supportive treatment which may involve administration of inotropic agents, assisted respiration, circulatory assistance, and acidification of the urine. Hemodialysis is not expected to be useful in the removal of flecainide from serum. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tambocor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flecaine Flecainida Flécaïnide Flecainide Flecainidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flecainide is a class Ic antiarrhythmic agent used to manage atrial fibrillation and paroxysmal supraventricular tachycardias (PSVT).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Flecainide interact? Information: •Drug A: Abatacept •Drug B: Flecainide •Severity: MAJOR •Description: The metabolism of Flecainide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In New Zealand and America, flecainide is indicated to prevent supraventricular arrhythmias and ventricular arrhythmias. In the United States, it is also indicated to prevent paroxysmal atrial fibrillation and flutter. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flecainide inhibits the action of sodium and potassium ion channels in the heart, raising the threshold for depolarization and correcting arrhythmias. Flecainide has a long duration of action, allowing for once daily dosing. The therapeutic index is narrow. Patients should not take this medication if there is already structural heart disease or left ventricular systolic dysfunction. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flecainide blocks fast inward sodium channels and slowly unbinds during diastole, prolonging the refractory period of the heart. This blockade also shortens the duration of action potentials through the Purkinjie fibers. Flecainide also prevents delayed rectifier potassium channels from opening, lengthening the action potential through ventricular and atrial muscle fibers. Finally, flecainide also blocks ryanodine receptor opening, reducing calcium release from sarcoplasmic reticulum, which reduces depolarization of cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral flecainide has a T max of 3-4h and a bioavialability of 90%. Taking flecainide with food or aluminum hydroxide antacids do not significantly affect the absorption of flecainide. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average volume of distribution in 8 male subjects is 5.0-13.4L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Flecainide is 40% bound to protein in serum, mainly to alpha-1-acid glycoprotein and minorly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flecainide is mainly metabolized to meta-O-dealkylated flecainide or the meta-O-dealkylated lactam of flecainide. Meta-O-dealkylated flecainide has 20% the activity of flecainide. Both of these metabolites are generally detected as glucuronide or sulfate conjugates. Flecainide’s metabolism involves the action of CYP2D6 and CYP1A2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 86% of a single oral dose is eliminated in the urine, with 42% as unchanged flecainide and 14% as meta-O-dealkylated flecainide, a similar amount of the meta-O-dealkylated lactam of flecainide, approximately 3% as an unidentified acid metabolite, and <1% as 2 other unknown metabolites. 5% is eliminated in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy subjects, intravenous flecainide has an average half life of 13 hours for a single dose and 16 hours for multiple oral doses. In patients with a ventricular premature complex, flecainide has a half life of 20 hours. The half life of meta-O-dealkylated flecainide, a major metabolite of flecainide, is 12.6h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance of intravenous flecainide is 4.6-12.1mL/min/kg in 8 male subjects. For oral flecainide, the clearance was 4-20mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 1346mg/kg and in mice is 170mg/kg. The subcutaneous LD 50 in rats is 215mg/kg and in mice is 188mg/kg. The oral TDLO in women is 20mg/kg and in men is 40mg/kg/2W. Patients experiencing an overdose may present with ECG abnormalities such as a lengthened PR interval, increased QRS duration, prolonged QT interval, increased amplitude of the T wave, reduced myocardial rate and contractility, hypotension, or death. Treat patients with symptomatic and supportive treatment which may involve administration of inotropic agents, assisted respiration, circulatory assistance, and acidification of the urine. Hemodialysis is not expected to be useful in the removal of flecainide from serum. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tambocor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flecaine Flecainida Flécaïnide Flecainide Flecainidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flecainide is a class Ic antiarrhythmic agent used to manage atrial fibrillation and paroxysmal supraventricular tachycardias (PSVT). Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Floxuridine interact?

•Drug A: Abatacept •Drug B: Floxuridine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Floxuridine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Also for the palliative management of liver cancer (usually administered by hepatic intra-arterial infusion). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Floxuridine is an anti-metabolite or a pyrimidine analog that works by disrupting the process S-phase of cell division, selectively targeting rapidly dividing cells. Due to the structural similarities, antimetabolites act as pyrimidine-like molecules and prevent normal pyrimidines from being incorporated into DNA. After successful biotransformation, floxuridine is converted into an active component, flurouracil, which blocks the enzyme which converts cytosine nucleosides into the deoxy derivative. Flurouracil also physically prevents the incorporation of thymidine nucleotides into the DNA strand by taking their place, further preventing DNA synthesis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Floxuridine rapidly undergoes catabolism to form 5-fluorouracil, which is the active component of the drug. 5-Fluorouracil primarily works by interfering with DNA synthesis; however, it may also inhibit the formation of fraudulent RNA via physical incorporation into the RNA. It is also an inhibitor of riboside phophorylase, preventing the utilization of pre-formed uracil in RNA synthesis. Floxuridine can also form 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), which is the monophosphate of floxuridine that inhibits thymidylate synthetase that plays a role in the methylation of deoxyuridylic acid to thymidylic acid during DNA synthesis. FUDR-MP thus interferes with DNA synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 215 mg/kg. Signs of overdose include nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluorodeoxyuridine 5FDU Deoxyfluorouridine Floxiridina Floxuridin Floxuridine Floxuridinum Fluorodeoxyuridine Fluoruridine deoxyribose •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Floxuridine is an antimetabolite used as palliative management for liver metastases of gastrointestinal malignancy.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Floxuridine interact? Information: •Drug A: Abatacept •Drug B: Floxuridine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Floxuridine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Also for the palliative management of liver cancer (usually administered by hepatic intra-arterial infusion). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Floxuridine is an anti-metabolite or a pyrimidine analog that works by disrupting the process S-phase of cell division, selectively targeting rapidly dividing cells. Due to the structural similarities, antimetabolites act as pyrimidine-like molecules and prevent normal pyrimidines from being incorporated into DNA. After successful biotransformation, floxuridine is converted into an active component, flurouracil, which blocks the enzyme which converts cytosine nucleosides into the deoxy derivative. Flurouracil also physically prevents the incorporation of thymidine nucleotides into the DNA strand by taking their place, further preventing DNA synthesis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Floxuridine rapidly undergoes catabolism to form 5-fluorouracil, which is the active component of the drug. 5-Fluorouracil primarily works by interfering with DNA synthesis; however, it may also inhibit the formation of fraudulent RNA via physical incorporation into the RNA. It is also an inhibitor of riboside phophorylase, preventing the utilization of pre-formed uracil in RNA synthesis. Floxuridine can also form 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), which is the monophosphate of floxuridine that inhibits thymidylate synthetase that plays a role in the methylation of deoxyuridylic acid to thymidylic acid during DNA synthesis. FUDR-MP thus interferes with DNA synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 215 mg/kg. Signs of overdose include nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluorodeoxyuridine 5FDU Deoxyfluorouridine Floxiridina Floxuridin Floxuridine Floxuridinum Fluorodeoxyuridine Fluoruridine deoxyribose •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Floxuridine is an antimetabolite used as palliative management for liver metastases of gastrointestinal malignancy. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Flucytosine interact?

•Drug A: Abatacept •Drug B: Flucytosine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Flucytosine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment (in combination with amphotericin B) of serious infections caused by susceptible strains of Candida (septicemia, endocarditis and urinary system infections) and/or Cryptococcus (meningitis and pulmonary infections). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flucytosine is an antimetabolite that acts as an antifungal agent with in vitro and in vivo activity against Candida and Cryptococcus. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 28-31% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2.4 to 4.8 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat: LD 50 = >15 gm/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ancobon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flucytosine is an antifungal indicated only to treat severe infections throughout the body caused by susceptible strains of Candida or Cryptococcus.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Flucytosine interact? Information: •Drug A: Abatacept •Drug B: Flucytosine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Flucytosine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment (in combination with amphotericin B) of serious infections caused by susceptible strains of Candida (septicemia, endocarditis and urinary system infections) and/or Cryptococcus (meningitis and pulmonary infections). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flucytosine is an antimetabolite that acts as an antifungal agent with in vitro and in vivo activity against Candida and Cryptococcus. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 28-31% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2.4 to 4.8 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat: LD 50 = >15 gm/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ancobon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flucytosine is an antifungal indicated only to treat severe infections throughout the body caused by susceptible strains of Candida or Cryptococcus. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Fludarabine interact?

•Drug A: Abatacept •Drug B: Fludarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fludarabine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability is 55% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 19-29% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m^2. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fludara •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fludarabina Fludarabine Fludarabinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fludarabine is a purine analog antimetabolite that inhibits DNA synthesis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Fludarabine interact? Information: •Drug A: Abatacept •Drug B: Fludarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fludarabine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Bioavailability is 55% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 19-29% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 20 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m^2. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fludara •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fludarabina Fludarabine Fludarabinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fludarabine is a purine analog antimetabolite that inhibits DNA synthesis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Fludrocortisone interact?

•Drug A: Abatacept •Drug B: Fludrocortisone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fludrocortisone is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fludrocortisone is indicated as partial replacement therapy for primary or secondary adrenocortical insufficiency in Addison's disease. It is also indicated for the treatment of salt-losing androgenital syndrome. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous aldosterone in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The main endogenous mineralocorticoid, aldosterone, is produced in the zona glomerulosa of the adrenal cortex - it acts on mineralocorticoid receptors in the kidneys to increase sodium reabsorption and potassium excretion, which in turn helps to regulate plasma electrolyte composition and blood pressure. In conditions of adrenal insufficiency, such as Addison’s disease, aldosterone is not produced (or is produced in insufficient quantities) and must be replaced by exogenous mineralocorticoids such as fludrocortisone. Fludrocortisone binding to mineralocorticoid receptors causes alterations to DNA transcription and translation of proteins that result in an increased density of sodium channels on the apical side of renal tubule cells and an increased density of Na -K -ATPase on the basolateral side. These increases in receptor density result in increased plasma sodium concentrations, and thus increased blood pressure, as well as a decreased plasma potassium concentration. Fludrocortisone may also exert a direct effect on plasma sodium levels via action at the Na -H exchanger found in the apical membrane of renal tubule cells. Fludrocortisone also acts on glucocorticoid receptors, albeit with a much lower affinity - the glucocorticoid potency of fludrocortisone is approximately 5-10 times that of endogenous cortisol, whereas its mineralocorticoid potency is 200-400 times greater. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the C max to be 0.0012 to 0.20 μg/L with a T max between 0.5 and 2 hours. The AUC 0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There exists is a paucity of information regarding the specific metabolic pathway in vivo of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An in vitro study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of fludrocortisone in rats is >1g/kg. Acute overdosage of fludrocortisone is likely to result in symptoms consistent with its adverse effect profile. Patients receiving a single large dose should be treated with plenty of water by mouth and should undergo monitoring of serum electrolytes, particularly potassium and sodium, and be treated appropriately for any developing imbalances. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Florinef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fludrocortisone is a mineralocorticoid used to treat adrenocortical insufficiency and salt-losing adrenogenital syndrome.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Fludrocortisone interact? Information: •Drug A: Abatacept •Drug B: Fludrocortisone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fludrocortisone is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fludrocortisone is indicated as partial replacement therapy for primary or secondary adrenocortical insufficiency in Addison's disease. It is also indicated for the treatment of salt-losing androgenital syndrome. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous aldosterone in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The main endogenous mineralocorticoid, aldosterone, is produced in the zona glomerulosa of the adrenal cortex - it acts on mineralocorticoid receptors in the kidneys to increase sodium reabsorption and potassium excretion, which in turn helps to regulate plasma electrolyte composition and blood pressure. In conditions of adrenal insufficiency, such as Addison’s disease, aldosterone is not produced (or is produced in insufficient quantities) and must be replaced by exogenous mineralocorticoids such as fludrocortisone. Fludrocortisone binding to mineralocorticoid receptors causes alterations to DNA transcription and translation of proteins that result in an increased density of sodium channels on the apical side of renal tubule cells and an increased density of Na -K -ATPase on the basolateral side. These increases in receptor density result in increased plasma sodium concentrations, and thus increased blood pressure, as well as a decreased plasma potassium concentration. Fludrocortisone may also exert a direct effect on plasma sodium levels via action at the Na -H exchanger found in the apical membrane of renal tubule cells. Fludrocortisone also acts on glucocorticoid receptors, albeit with a much lower affinity - the glucocorticoid potency of fludrocortisone is approximately 5-10 times that of endogenous cortisol, whereas its mineralocorticoid potency is 200-400 times greater. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the C max to be 0.0012 to 0.20 μg/L with a T max between 0.5 and 2 hours. The AUC 0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There exists is a paucity of information regarding the specific metabolic pathway in vivo of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An in vitro study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of fludrocortisone in rats is >1g/kg. Acute overdosage of fludrocortisone is likely to result in symptoms consistent with its adverse effect profile. Patients receiving a single large dose should be treated with plenty of water by mouth and should undergo monitoring of serum electrolytes, particularly potassium and sodium, and be treated appropriately for any developing imbalances. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Florinef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fludrocortisone is a mineralocorticoid used to treat adrenocortical insufficiency and salt-losing adrenogenital syndrome. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Flunarizine interact?

•Drug A: Abatacept •Drug B: Flunarizine •Severity: MODERATE •Description: The metabolism of Flunarizine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 85% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, to two metabolites via N-dealylation and hydroxylation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 18 days •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): -Flunarizine should be used with care in patients with depression or those being prescribed other agents, such as phenothiazines, concurrently, which may cause extrapyramidal side-effects. -Acute overdosage has been reported and the observed symptoms were sedation, agitation and tachycardia. -Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flunarizina Flunarizine Flunarizinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunarizine is a selective calcium-entry blocker used as migraine prophylaxis in patients with severe and frequent episodes who have not responded adequately to more common treatments.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Flunarizine interact? Information: •Drug A: Abatacept •Drug B: Flunarizine •Severity: MODERATE •Description: The metabolism of Flunarizine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 85% following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, to two metabolites via N-dealylation and hydroxylation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 18 days •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): -Flunarizine should be used with care in patients with depression or those being prescribed other agents, such as phenothiazines, concurrently, which may cause extrapyramidal side-effects. -Acute overdosage has been reported and the observed symptoms were sedation, agitation and tachycardia. -Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flunarizina Flunarizine Flunarizinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunarizine is a selective calcium-entry blocker used as migraine prophylaxis in patients with severe and frequent episodes who have not responded adequately to more common treatments. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Flunisolide interact?

•Drug A: Abatacept •Drug B: Flunisolide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Flunisolide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the maintenance treatment of asthma as a prophylactic therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunisolide is a synthetic corticosteroid. It is administered either as an oral metered-dose inhaler for the treatment of asthma or as a nasal spray for treating allergic rhinitis. Corticosteroids are naturally occurring hormones that prevent or suppress inflammation and immune responses. When given as an intranasal spray, flunisolide reduces watery nasal discharge (rhinorrhea), nasal congestion, postnasal drip, sneezing, and itching oat the back of the throat that are common allergic symptoms. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flunisolide is a glucocorticoid receptor agonist. The antiinflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. The immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Flunisolide binds to plasma transcortin, and it becomes active when it is not bound to transcortin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed rapidly •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 40% after oral inhalation •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic, converted to the S beta-OH metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1.8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flunisolida Flunisolide Flunisolidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunisolide is an inhaled corticosteroid used as a prophylactic therapy in the maintenance treatment of asthma.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Flunisolide interact? Information: •Drug A: Abatacept •Drug B: Flunisolide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Flunisolide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the maintenance treatment of asthma as a prophylactic therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunisolide is a synthetic corticosteroid. It is administered either as an oral metered-dose inhaler for the treatment of asthma or as a nasal spray for treating allergic rhinitis. Corticosteroids are naturally occurring hormones that prevent or suppress inflammation and immune responses. When given as an intranasal spray, flunisolide reduces watery nasal discharge (rhinorrhea), nasal congestion, postnasal drip, sneezing, and itching oat the back of the throat that are common allergic symptoms. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flunisolide is a glucocorticoid receptor agonist. The antiinflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. The immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Flunisolide binds to plasma transcortin, and it becomes active when it is not bound to transcortin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed rapidly •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 40% after oral inhalation •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic, converted to the S beta-OH metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1.8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flunisolida Flunisolide Flunisolidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunisolide is an inhaled corticosteroid used as a prophylactic therapy in the maintenance treatment of asthma. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Flunitrazepam interact?

•Drug A: Abatacept •Drug B: Flunitrazepam •Severity: MODERATE •Description: The metabolism of Flunitrazepam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For short-term treatment of severe insomnias, that are not responsive to other hypnotics. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 50% (suppository) and 64-77% (oral) •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 18-26 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunitrazepam is a benzodiazepine used to manage anxiety disorders and insomnia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Flunitrazepam interact? Information: •Drug A: Abatacept •Drug B: Flunitrazepam •Severity: MODERATE •Description: The metabolism of Flunitrazepam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For short-term treatment of severe insomnias, that are not responsive to other hypnotics. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 50% (suppository) and 64-77% (oral) •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 18-26 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flunitrazepam is a benzodiazepine used to manage anxiety disorders and insomnia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluocinolone acetonide interact?

•Drug A: Abatacept •Drug B: Fluocinolone acetonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluocinolone acetonide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluocinolone acetonide has been used extensively in different medical areas. -In dermatology, it is extensively used for the relief of inflammatory dermatosis, dermatitis, psoriasis, hypertrophic tissues, keloid tissues and atopic dermatitis. -It has been used in shampoo products as a low to medium potency corticosteroid for the treatment of seborrheic dermatitis of the scalp. -In ear drops, it is used as a low to medium potency corticosteroid for the treatment of chronic eczematous external otitis in adults and pediatric patients 2 years and older. -As an intravitreal implant, it is indicated for the treatment of diabetic macular edema with patients that have been previously treated with a course of corticosteroids and no clinically significant rise in intraocular pressure. -Fluocinolone acetonide was announced on October 15, 2018 to be FDA approved for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. -Some reports have indicated the use of fluocinolone acetonide as a vasoprotective agent and for its use in the treatment of first-degree hemorrhoids. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluocinolone acetonide is a synthetic anti-inflammatory corticosteroid and thus, the effect of its interaction with the body produces vasoconstriction and suppression of membrane permeability, mitotic activity, immune response and release of inflammatory mediators. For its ophthalmic indications, fluocinolone acetonide is administered as intravitreal micro-insert. This preparation was observed in clinical trials to reduce the recurrence of uveitis flares by 2 fold when compared with the non treated patients even after six months after initial administration. As well the intraocular pressure seemed to increase slightly with the presence of the fluocinolone implant but it is important to monitor intraocular pressure. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluocinolone acetonide is a corticosteroid and thus, it can be inferred that it acts by inhibiting the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, collagen deposition, and scar formation. Some reports have indicated that fluocinolone acetonide presents a high binding affinity for the glucocorticoid receptor. After binding the receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements in the promoter region of the target genes. This effect promotes the induction of phospholipase A2 inhibitory proteins (lipocortins). Through this mechanism of action, it is thought that fluocinolone induces mainly one of the lipocortins, annexin 1, which will later mediate the synthesis of inflammatory mediators such as prostaglandins and leukotrienes by inhibiting the release of arachidonic acid which is the precursor of all these inflammatory mediators. Hence, the induction of these proteins will prevent the release of arachidonic acid by phospholipase A2. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): When administered as an eye implant, fluocinolone acetonide presents a sustained delivery for even 12 months in which there can be observed a sustained release. The concentration of fluocinolone acetonide are generally higher in the vitreous and retina with a little dispersion to the aqueous humor. There are reports indicating that topical administration of fluocinolone acetonide produces a percutaneous absorption which is determined by the vehicle, integrity of the epidermal barrier and the use of occlusive dressing. Independently of the route of administration, the systemic absorption of fluocinolone acetonide is below 0.1 ng/ml which indicates that the systemic distribution is very minimal and the effect of fluocinolone is mainly local. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following absorption, fluocinolone acetonide metabolism is primarily hepatic. It is important to mention that the systemically absorbed dose is very minimal. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluocinolone acetonide is mainly excreted by the kidneys. It is important to mention that the systemically absorbed dose is very minimal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of fluocinolone acetonide ranges between 1.3-1.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal and the concentration in urine is lower than the minimum quantitation limit. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Studies to determine the carcinogenic and its effect in fertility have not been performed. It is important to consider that several corticosteroids have been shown to present genotoxic potential but fluocinolone acetonide was shown to not be genotoxic in the Ames test and mouse lymphoma TK assay. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Capex, Derma-Smoothe/FS, Derma-smoothe FS, Dermotic, Flac, Iluvien, Neo-synalar, Otixal, Otovel, Retisert, Synalar, Tri-luma, Yutiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acétonide de fluocinolone acetónido de fluocinolona fluocinolon acetonid Fluocinolone acetonide fluocinoloni acetonidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluocinolone acetonide is a corticosteroid used to treat skin conditions, eczematous otitis externa, diabetic macular edema, and non-infectious uveitis of the posterior segment of the eye.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Fluocinolone acetonide interact? Information: •Drug A: Abatacept •Drug B: Fluocinolone acetonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluocinolone acetonide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluocinolone acetonide has been used extensively in different medical areas. -In dermatology, it is extensively used for the relief of inflammatory dermatosis, dermatitis, psoriasis, hypertrophic tissues, keloid tissues and atopic dermatitis. -It has been used in shampoo products as a low to medium potency corticosteroid for the treatment of seborrheic dermatitis of the scalp. -In ear drops, it is used as a low to medium potency corticosteroid for the treatment of chronic eczematous external otitis in adults and pediatric patients 2 years and older. -As an intravitreal implant, it is indicated for the treatment of diabetic macular edema with patients that have been previously treated with a course of corticosteroids and no clinically significant rise in intraocular pressure. -Fluocinolone acetonide was announced on October 15, 2018 to be FDA approved for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. -Some reports have indicated the use of fluocinolone acetonide as a vasoprotective agent and for its use in the treatment of first-degree hemorrhoids. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluocinolone acetonide is a synthetic anti-inflammatory corticosteroid and thus, the effect of its interaction with the body produces vasoconstriction and suppression of membrane permeability, mitotic activity, immune response and release of inflammatory mediators. For its ophthalmic indications, fluocinolone acetonide is administered as intravitreal micro-insert. This preparation was observed in clinical trials to reduce the recurrence of uveitis flares by 2 fold when compared with the non treated patients even after six months after initial administration. As well the intraocular pressure seemed to increase slightly with the presence of the fluocinolone implant but it is important to monitor intraocular pressure. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluocinolone acetonide is a corticosteroid and thus, it can be inferred that it acts by inhibiting the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, collagen deposition, and scar formation. Some reports have indicated that fluocinolone acetonide presents a high binding affinity for the glucocorticoid receptor. After binding the receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements in the promoter region of the target genes. This effect promotes the induction of phospholipase A2 inhibitory proteins (lipocortins). Through this mechanism of action, it is thought that fluocinolone induces mainly one of the lipocortins, annexin 1, which will later mediate the synthesis of inflammatory mediators such as prostaglandins and leukotrienes by inhibiting the release of arachidonic acid which is the precursor of all these inflammatory mediators. Hence, the induction of these proteins will prevent the release of arachidonic acid by phospholipase A2. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): When administered as an eye implant, fluocinolone acetonide presents a sustained delivery for even 12 months in which there can be observed a sustained release. The concentration of fluocinolone acetonide are generally higher in the vitreous and retina with a little dispersion to the aqueous humor. There are reports indicating that topical administration of fluocinolone acetonide produces a percutaneous absorption which is determined by the vehicle, integrity of the epidermal barrier and the use of occlusive dressing. Independently of the route of administration, the systemic absorption of fluocinolone acetonide is below 0.1 ng/ml which indicates that the systemic distribution is very minimal and the effect of fluocinolone is mainly local. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following absorption, fluocinolone acetonide metabolism is primarily hepatic. It is important to mention that the systemically absorbed dose is very minimal. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluocinolone acetonide is mainly excreted by the kidneys. It is important to mention that the systemically absorbed dose is very minimal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of fluocinolone acetonide ranges between 1.3-1.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal and the concentration in urine is lower than the minimum quantitation limit. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Studies to determine the carcinogenic and its effect in fertility have not been performed. It is important to consider that several corticosteroids have been shown to present genotoxic potential but fluocinolone acetonide was shown to not be genotoxic in the Ames test and mouse lymphoma TK assay. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Capex, Derma-Smoothe/FS, Derma-smoothe FS, Dermotic, Flac, Iluvien, Neo-synalar, Otixal, Otovel, Retisert, Synalar, Tri-luma, Yutiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acétonide de fluocinolone acetónido de fluocinolona fluocinolon acetonid Fluocinolone acetonide fluocinoloni acetonidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluocinolone acetonide is a corticosteroid used to treat skin conditions, eczematous otitis externa, diabetic macular edema, and non-infectious uveitis of the posterior segment of the eye. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Fluocinonide interact?

•Drug A: Abatacept •Drug B: Fluocinonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluocinonide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): A topical anti-inflammatory product for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. It mediates its effects to relieve itching, redness, dryness, crusting, scaling, inflammation, and discomfort associated with inflammatory skin conditions. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. Fluocinonide binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. Cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In another words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Like other glucocorticoid agents Fluocinolone acetonide acts as a physiological antagonist to insulin by decreasing glycogenesis (formation of glycogen). It also promotes the breakdown of lipids (lipolysis), and proteins, leading to the mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is also decreased glycogen formation in the liver. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. In general, percutaneous absorption is minimal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects may include acne-like eruptions, burning, dryness, excessive hair growth, infection of the skin, irritation, itching, lack of skin colour, prickly heat, skin inflammation, skin loss or softening, stretch marks. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lidemol, Lidex, Lyderm, Tiamol, Vanos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluocinonide is a high potency corticosteroid commonly used topically for a number of inflammatory skin conditions.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Fluocinonide interact? Information: •Drug A: Abatacept •Drug B: Fluocinonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluocinonide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): A topical anti-inflammatory product for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. It mediates its effects to relieve itching, redness, dryness, crusting, scaling, inflammation, and discomfort associated with inflammatory skin conditions. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. Fluocinonide binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. Cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In another words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Like other glucocorticoid agents Fluocinolone acetonide acts as a physiological antagonist to insulin by decreasing glycogenesis (formation of glycogen). It also promotes the breakdown of lipids (lipolysis), and proteins, leading to the mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is also decreased glycogen formation in the liver. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. In general, percutaneous absorption is minimal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects may include acne-like eruptions, burning, dryness, excessive hair growth, infection of the skin, irritation, itching, lack of skin colour, prickly heat, skin inflammation, skin loss or softening, stretch marks. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lidemol, Lidex, Lyderm, Tiamol, Vanos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluocinonide is a high potency corticosteroid commonly used topically for a number of inflammatory skin conditions. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Fluorometholone interact?

•Drug A: Abatacept •Drug B: Fluorometholone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluorometholone is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the ophthalmic treatment of corticosteroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Corticosteroids such as fluorometholone inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Their primary target is the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects may include acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. LD 50 = 234 mg/kg (rats) •Brand Names (Drug A): Orencia •Brand Names (Drug B): FML, FML Forte Liquifilm, FML-S, Flarex, Fluor-OP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluorometholon Fluorométholone Fluorometholone Fluorometholonum Fluorometolona •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluorometholone is an ophthalmic corticosteroid used for the relief of inflammation located in both the palpebral and bulbar conjunctiva, the cornea, and the anterior segment of the globe of the eye.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Fluorometholone interact? Information: •Drug A: Abatacept •Drug B: Fluorometholone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Fluorometholone is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the ophthalmic treatment of corticosteroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Corticosteroids such as fluorometholone inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Their primary target is the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects may include acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. LD 50 = 234 mg/kg (rats) •Brand Names (Drug A): Orencia •Brand Names (Drug B): FML, FML Forte Liquifilm, FML-S, Flarex, Fluor-OP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluorometholon Fluorométholone Fluorometholone Fluorometholonum Fluorometolona •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluorometholone is an ophthalmic corticosteroid used for the relief of inflammation located in both the palpebral and bulbar conjunctiva, the cornea, and the anterior segment of the globe of the eye. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Fluorouracil interact?

•Drug A: Abatacept •Drug B: Fluorouracil •Severity: MAJOR •Description: The metabolism of Fluorouracil can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 28-100% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 8-12% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10-20 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =230mg/kg (orally in mice) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Actikerall, Carac, Efudex, Fluoroplex, Tolak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluoracil 5-Fluorouracil 5-Fluracil 5-FU Fluoro Uracil Fluorouracil Fluorouracilo Fluorouracilum Fluouracil •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluorouracil is a pyrimidine analog used to treat basal cell carcinomas, and as an injection in palliative cancer treatment.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Fluorouracil interact? Information: •Drug A: Abatacept •Drug B: Fluorouracil •Severity: MAJOR •Description: The metabolism of Fluorouracil can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 28-100% •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 8-12% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10-20 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =230mg/kg (orally in mice) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Actikerall, Carac, Efudex, Fluoroplex, Tolak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-Fluoracil 5-Fluorouracil 5-Fluracil 5-FU Fluoro Uracil Fluorouracil Fluorouracilo Fluorouracilum Fluouracil •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluorouracil is a pyrimidine analog used to treat basal cell carcinomas, and as an injection in palliative cancer treatment. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Fluoxetine interact?

•Drug A: Abatacept •Drug B: Fluoxetine •Severity: MODERATE •Description: The metabolism of Fluoxetine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression. Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT 2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 94% of fluoxetine is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluoxetine is primarily eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1.2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prozac, Sarafem, Symbyax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxetin Fluoxetina Fluoxétine Fluoxetine Fluoxetinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluoxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluoxetine interact? Information: •Drug A: Abatacept •Drug B: Fluoxetine •Severity: MODERATE •Description: The metabolism of Fluoxetine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression. Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT 2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 94% of fluoxetine is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluoxetine is primarily eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1.2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prozac, Sarafem, Symbyax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxetin Fluoxetina Fluoxétine Fluoxetine Fluoxetinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluoxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Flurazepam interact?

•Drug A: Abatacept •Drug B: Flurazepam •Severity: MODERATE •Description: The metabolism of Flurazepam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For short-term and intermittent use in patients with recurring insomnia and poor sleeping habits •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Furthermore, it decreases sleep latency and number of awakenings for a consequent increase in total sleep time. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flurazepam binds to an allosteric site on GABA-A receptors. Binding potentiates the action of GABA on GABA-A receptors by opening the chloride channel within the receptor, causing chloride influx and hyperpolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Flurazepam hydrochloride is rapidly (30 minutes) absorbed from the gastrointestinal tract •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 83% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flurazepam is rapidly metabolized and is excreted primarily in the urine. Both hydroxyethyl flurazepam (the major metabolite) and N-desalkyl flurazepam are active. The N-desalkyl metabolite is slowly excreted in the urine as the conjugated form •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flurazepam is rapidly metabolized and is excreted primarily in the urine. Less than 1% of the dose is excreted in the urine as N1-desalkyl-flurazepam. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean apparent half-life of flurazepam is 2.3 hours. The half life of elimination of N1-des-alkyl- flurazepam ranged from 47 to 100 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Coma, confusion, low blood pressure, sleepiness •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flurazepam is a long-acting benzodiazepine with a rapid onset of action that is commonly used to treat insomnia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Flurazepam interact? Information: •Drug A: Abatacept •Drug B: Flurazepam •Severity: MODERATE •Description: The metabolism of Flurazepam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For short-term and intermittent use in patients with recurring insomnia and poor sleeping habits •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Furthermore, it decreases sleep latency and number of awakenings for a consequent increase in total sleep time. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flurazepam binds to an allosteric site on GABA-A receptors. Binding potentiates the action of GABA on GABA-A receptors by opening the chloride channel within the receptor, causing chloride influx and hyperpolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Flurazepam hydrochloride is rapidly (30 minutes) absorbed from the gastrointestinal tract •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 83% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flurazepam is rapidly metabolized and is excreted primarily in the urine. Both hydroxyethyl flurazepam (the major metabolite) and N-desalkyl flurazepam are active. The N-desalkyl metabolite is slowly excreted in the urine as the conjugated form •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flurazepam is rapidly metabolized and is excreted primarily in the urine. Less than 1% of the dose is excreted in the urine as N1-desalkyl-flurazepam. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean apparent half-life of flurazepam is 2.3 hours. The half life of elimination of N1-des-alkyl- flurazepam ranged from 47 to 100 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Coma, confusion, low blood pressure, sleepiness •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flurazepam is a long-acting benzodiazepine with a rapid onset of action that is commonly used to treat insomnia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Abatacept and Flurbiprofen interact?

•Drug A: Abatacept •Drug B: Flurbiprofen •Severity: MODERATE •Description: The metabolism of Flurbiprofen can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Flurbiprofen tablets are indicated for the acute or long-term symptomatic treatment of rheumatoid arthritis, osteorarthritis and anklosing spondylitis. It may also be used to treat pain associated with dysmenorrhea and mild to moderate pain accompanied by inflammation (e.g. bursitis, tendonitis, soft tissue trauma). Topical ophthalmic formulations may be used pre-operatively to prevent intraoperative miosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flurbiprofen, a nonsteroidal anti-inflammatory agent (NSAIA) of the propionic acid class, is structually and pharmacologically related to fenoprofen, ibuprofen, and ketoprofen, and has similar pharmacological actions to other prototypica NSAIAs. Flurbiprofen exhibits antiinflammatory, analgesic, and antipyretic activities. The commercially available flurbiprofen is a racemic mixture of (+)S- and (-) R-enantiomers. The S-enantiomer appears to possess most of the anti-inflammatory, while both enantiomers may possess analgesic activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other NSAIAs, the anti-inflammatory effect of flurbiprofen occurs via reversible inhibition of cyclooxygenase (COX), the enzyme responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2) in the prostaglandin synthesis pathway. This effectively decreases the concentration of prostaglandins involved in inflammation, pain, swelling and fever. Flurbiprofen is a non-selective COX inhibitor and inhibits the activity of both COX-1 and -2. It is also one of the most potent NSAIAs in terms of prostaglandin inhibitory activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fluribiprofen is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are reached 0.5 - 4 hours after oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 14 L [Normal Healthy Adults] 12 L [Geriatric Arthritis Patients] 10 L [End Stage Renal Disease Patients] 14 L [Alcoholic Cirrhosis Patients] 0.12 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99% bound, primarily to albumin. Binds to a different primary binding site on albumin than anticoagulants, sulfonamides and phenytoin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4’-hydroxy-flurbiprofen. The 4’-hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flurbiprofen is poorly excreted into human milk. Following dosing with flurbiprofen, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Renal elimination is a significant pathway of elimination of flurbiprofen metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): R-flurbiprofen, 4.7 hours; S-flurbiprofen, 5.7 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =10 mg/kg (orally in dogs). Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of flurbiprofen. Flurbiprofen may increase blood pressure and/or cause fluid retention and edema. Use caution in patients with fluid retention or heart failure. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) may occur. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Although rarely documented in the case of flurbiprofen, oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flurbiprofen Flurbiprofene Flurbiprofeno Flurbiprofenum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flurbiprofen is an NSAID used to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Flurbiprofen interact? Information: •Drug A: Abatacept •Drug B: Flurbiprofen •Severity: MODERATE •Description: The metabolism of Flurbiprofen can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Flurbiprofen tablets are indicated for the acute or long-term symptomatic treatment of rheumatoid arthritis, osteorarthritis and anklosing spondylitis. It may also be used to treat pain associated with dysmenorrhea and mild to moderate pain accompanied by inflammation (e.g. bursitis, tendonitis, soft tissue trauma). Topical ophthalmic formulations may be used pre-operatively to prevent intraoperative miosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flurbiprofen, a nonsteroidal anti-inflammatory agent (NSAIA) of the propionic acid class, is structually and pharmacologically related to fenoprofen, ibuprofen, and ketoprofen, and has similar pharmacological actions to other prototypica NSAIAs. Flurbiprofen exhibits antiinflammatory, analgesic, and antipyretic activities. The commercially available flurbiprofen is a racemic mixture of (+)S- and (-) R-enantiomers. The S-enantiomer appears to possess most of the anti-inflammatory, while both enantiomers may possess analgesic activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Similar to other NSAIAs, the anti-inflammatory effect of flurbiprofen occurs via reversible inhibition of cyclooxygenase (COX), the enzyme responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2) in the prostaglandin synthesis pathway. This effectively decreases the concentration of prostaglandins involved in inflammation, pain, swelling and fever. Flurbiprofen is a non-selective COX inhibitor and inhibits the activity of both COX-1 and -2. It is also one of the most potent NSAIAs in terms of prostaglandin inhibitory activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fluribiprofen is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are reached 0.5 - 4 hours after oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 14 L [Normal Healthy Adults] 12 L [Geriatric Arthritis Patients] 10 L [End Stage Renal Disease Patients] 14 L [Alcoholic Cirrhosis Patients] 0.12 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99% bound, primarily to albumin. Binds to a different primary binding site on albumin than anticoagulants, sulfonamides and phenytoin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4’-hydroxy-flurbiprofen. The 4’-hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flurbiprofen is poorly excreted into human milk. Following dosing with flurbiprofen, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Renal elimination is a significant pathway of elimination of flurbiprofen metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): R-flurbiprofen, 4.7 hours; S-flurbiprofen, 5.7 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =10 mg/kg (orally in dogs). Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of flurbiprofen. Flurbiprofen may increase blood pressure and/or cause fluid retention and edema. Use caution in patients with fluid retention or heart failure. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) may occur. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Although rarely documented in the case of flurbiprofen, oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flurbiprofen Flurbiprofene Flurbiprofeno Flurbiprofenum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flurbiprofen is an NSAID used to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Flutamide interact?

•Drug A: Abatacept •Drug B: Flutamide •Severity: MODERATE •Description: The metabolism of Flutamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flutamide is a nonsteroidal antiandrogen. In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g. castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and completely absorbed. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94-96% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Eulexin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flutamid Flutamida Flutamide Flutamidum NFBA Niftolid Niftolide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flutamide is an antiandrogen used for locally confined stage B2-C and D-2 metastatic prostate carcinoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Flutamide interact? Information: •Drug A: Abatacept •Drug B: Flutamide •Severity: MODERATE •Description: The metabolism of Flutamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Flutamide is a nonsteroidal antiandrogen. In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g. castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and completely absorbed. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94-96% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Eulexin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Flutamid Flutamida Flutamide Flutamidum NFBA Niftolid Niftolide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Flutamide is an antiandrogen used for locally confined stage B2-C and D-2 metastatic prostate carcinoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluticasone furoate interact?

•Drug A: Abatacept •Drug B: Fluticasone furoate •Severity: MODERATE •Description: The metabolism of Fluticasone furoate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone furoate is indicated for once-daily maintenance (i.e. prophylactic) treatment of asthma in patients ≥5 years old. Fluticasone furoate is available in two combination medications - one in combination with vilanterol and one in combination with both vilanterol and umeclidinium - which are both indicated for the management of chronic obstructive pulmonary disease (COPD) and for the treatment of asthma in patients ≥18 years old for the vilanterol-umeclidinium-fluticasone product and ≥5 years old for the vilanterol-fluticasone product. Fluticasone furoate is available over the counter as a nasal spray for the symptomatic treatment of hay fever and other upper respiratory allergies in patients ≥2 years old. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man. Inhaled fluticasone furoate at repeat doses of up to 400 mcg in healthy subjects was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Reductions in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. For subjects with asthma, a randomized, double-blind, parallel-group trial in 104 pediatric subjects showed no difference between once-daily treatment with 50 mcg fluticasone compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC (0-24) following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 subjects with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24), and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression. A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation. Intranasal exposure of fluticasone furoate also results in patients swallowing a larger portion of the dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%, predominantly to albumin (96%) and α1-acid glycoprotein (90%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Fluticasone furoate is also hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose, and that in urine was approximately 1% of the total dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 with a total plasma clearance of 65.4 L/hr. A study of 24 healthy Caucasian males also showed a clearance of 71.8L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used with caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well-controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for a reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arnuity Ellipta, Avamys, Breo Ellipta, Flonase Sensimist, Trelegy Ellipta, Veramyst •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone furoate is an inhaled corticosteroid that can be used as maintenance treatment of asthma and/or chronic obstructive pulmonary disease (COPD) depending on the product. Also available as a nasal spray to manage symptoms of allergic rhinitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluticasone furoate interact? Information: •Drug A: Abatacept •Drug B: Fluticasone furoate •Severity: MODERATE •Description: The metabolism of Fluticasone furoate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone furoate is indicated for once-daily maintenance (i.e. prophylactic) treatment of asthma in patients ≥5 years old. Fluticasone furoate is available in two combination medications - one in combination with vilanterol and one in combination with both vilanterol and umeclidinium - which are both indicated for the management of chronic obstructive pulmonary disease (COPD) and for the treatment of asthma in patients ≥18 years old for the vilanterol-umeclidinium-fluticasone product and ≥5 years old for the vilanterol-fluticasone product. Fluticasone furoate is available over the counter as a nasal spray for the symptomatic treatment of hay fever and other upper respiratory allergies in patients ≥2 years old. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Though effective for the treatment of asthma, corticosteroids may not affect symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone furoate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (approximately 1.3%), and the minimal pharmacological activity of the metabolites detected in man. Inhaled fluticasone furoate at repeat doses of up to 400 mcg in healthy subjects was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Reductions in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. For subjects with asthma, a randomized, double-blind, parallel-group trial in 104 pediatric subjects showed no difference between once-daily treatment with 50 mcg fluticasone compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC (0-24) following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 subjects with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24), and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression. A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo and positive-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects asthma symptoms is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administrated by inhalation was 13.9%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in subjects with asthma was 26% lower than observed in healthy subjects. Following repeat dosing of inhaled fluticasone furoate, steady state was achieved within 6 days with up to 2.6-fold accumulation. Intranasal exposure of fluticasone furoate also results in patients swallowing a larger portion of the dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%, predominantly to albumin (96%) and α1-acid glycoprotein (90%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Fluticasone furoate is also hydrolyzed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intravenous dosing with radiolabeled fluticasone furoate, mass balance showed 90% of radiolabel in the feces and 2% in the urine. Following oral dosing, radiolabel recovered in feces was 101% of the total dose, and that in urine was approximately 1% of the total dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration to healthy subjects, fluticasone furoate was cleared from systemic circulation principally by hepatic metabolism via CYP3A4 with a total plasma clearance of 65.4 L/hr. A study of 24 healthy Caucasian males also showed a clearance of 71.8L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used with caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well-controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for a reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arnuity Ellipta, Avamys, Breo Ellipta, Flonase Sensimist, Trelegy Ellipta, Veramyst •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone furoate is an inhaled corticosteroid that can be used as maintenance treatment of asthma and/or chronic obstructive pulmonary disease (COPD) depending on the product. Also available as a nasal spray to manage symptoms of allergic rhinitis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluticasone propionate interact?

•Drug A: Abatacept •Drug B: Fluticasone propionate •Severity: MODERATE •Description: The metabolism of Fluticasone propionate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxis as well as inflammatory and pruritic dermatoses. Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Systemically, fluticasone propionate activates glucocorticoid receptors, and inhibits lung eosinophilia in rats. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone propionate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. Fluticasone propionate activates glucocorticoid receptors and inhibits lung eosinophilia in rats. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of intravenous fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone propionate is 99% protein bound in serum. Topical fluticasone propionate is only 91% protein bound in serum however. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone propionate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7.8 hours for intravenous fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 1093mL/min for fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone propionate's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Advair, Airduo, Airduo Respiclick, Aller-flo, Armonair, Beser, Cutivate, Dymista, Flonase, Flovent, Fluticare, Ticanase, Wixela, Xhance •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone propionate is a glucocorticoid used to treat asthma, inflammatory pruritic dermatoses, and nonallergic rhinitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluticasone propionate interact? Information: •Drug A: Abatacept •Drug B: Fluticasone propionate •Severity: MODERATE •Description: The metabolism of Fluticasone propionate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxis as well as inflammatory and pruritic dermatoses. Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Systemically, fluticasone propionate activates glucocorticoid receptors, and inhibits lung eosinophilia in rats. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone propionate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. Fluticasone propionate activates glucocorticoid receptors and inhibits lung eosinophilia in rats. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of intravenous fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone propionate is 99% protein bound in serum. Topical fluticasone propionate is only 91% protein bound in serum however. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone propionate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7.8 hours for intravenous fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 1093mL/min for fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone propionate's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Advair, Airduo, Airduo Respiclick, Aller-flo, Armonair, Beser, Cutivate, Dymista, Flonase, Flovent, Fluticare, Ticanase, Wixela, Xhance •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone propionate is a glucocorticoid used to treat asthma, inflammatory pruritic dermatoses, and nonallergic rhinitis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluticasone interact?

•Drug A: Abatacept •Drug B: Fluticasone •Severity: MODERATE •Description: The metabolism of Fluticasone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone's 2 esters are indicated as inhalers for the treatment and management of asthma by prophylaxis as well as inflammatory and pruritic dermatoses. A Fluticasone propionate nasal spray is indicated for managing nonallergic rhinitis while the Fluticasone furoate nasal spray is indicated for treating season and perennial allergic rhinitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Systemically, in vitro experiments show Fluticasone furoate activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone furoate and Fluticasone propionate work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show Fluticasone furoate activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Intranasal exposure of Fluticasone furoate results in patients swallowing a larger portion of the dose. However, absorption is poor and metabolism is high, therefore there is negligible systemic exposure with a nasal bioavailability of 0.50% and oral bioavialability of 1.26%. Inhaled bioavailability is 13.9%. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 6.3-18.4%. Intranasal bioavailability of Fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of Fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 608L at steady state for intravenous administration of Fluticasone furoate. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. The volume of distribution of intravenous Fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%. Fluticasone propionate is 99% protein bound in serum. Topical Fluticasone propionate is only 91% protein bound in serum however. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone furoate and Fluticasone propionate are cleared from hepatic metabolism by cytochrome P450 3A4. Both are hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluticasone furoate is eliminated ≥90% in the feces and 1-2% in the urine. Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15.1 hours for intranasal Fluticasone furoate and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation. 7.8 hours for intravenous Fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 57.8L/h for Fluticasone furoate. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration. 1093mL/min for Fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used in caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment. Fluticasone propionate 's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous Fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with Fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with Fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of Fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone is a corticosteroid indicated in the treatment of corticosteroid responsive dermatoses, asthma, and COPD.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluticasone interact? Information: •Drug A: Abatacept •Drug B: Fluticasone •Severity: MODERATE •Description: The metabolism of Fluticasone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fluticasone's 2 esters are indicated as inhalers for the treatment and management of asthma by prophylaxis as well as inflammatory and pruritic dermatoses. A Fluticasone propionate nasal spray is indicated for managing nonallergic rhinitis while the Fluticasone furoate nasal spray is indicated for treating season and perennial allergic rhinitis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Systemically, in vitro experiments show Fluticasone furoate activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluticasone furoate and Fluticasone propionate work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show Fluticasone furoate activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Intranasal exposure of Fluticasone furoate results in patients swallowing a larger portion of the dose. However, absorption is poor and metabolism is high, therefore there is negligible systemic exposure with a nasal bioavailability of 0.50% and oral bioavialability of 1.26%. Inhaled bioavailability is 13.9%. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 6.3-18.4%. Intranasal bioavailability of Fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of Fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 608L at steady state for intravenous administration of Fluticasone furoate. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration. The volume of distribution of intravenous Fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fluticasone furoate is >99% protein bound in serum and may be as high as 99.6%. Fluticasone propionate is 99% protein bound in serum. Topical Fluticasone propionate is only 91% protein bound in serum however. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluticasone furoate and Fluticasone propionate are cleared from hepatic metabolism by cytochrome P450 3A4. Both are hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fluticasone furoate is eliminated ≥90% in the feces and 1-2% in the urine. Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15.1 hours for intranasal Fluticasone furoate and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation. 7.8 hours for intravenous Fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 57.8L/h for Fluticasone furoate. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration. 1093mL/min for Fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used in caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment. Fluticasone propionate 's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous Fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with Fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with Fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of Fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluticasone is a corticosteroid indicated in the treatment of corticosteroid responsive dermatoses, asthma, and COPD. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluvastatin interact?

•Drug A: Abatacept •Drug B: Fluvastatin •Severity: MODERATE •Description: The metabolism of Fluvastatin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): To be used as an adjunct to dietary therapy to prevent cardiovascular events. May be used as secondary prevention in patients with coronary heart disease (CHD) to reduce the risk of requiring coronary revascularization procedures, for reducing progression of coronary atherosclerosis in hypercholesterolemic patients with CHD, and for the treatment of primary hypercholesterolemia and mixed dyslidipidemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluvastatin, the first synthetically-derived HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Fluvastatin acts primarily in the liver. It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total and LDL cholesterol. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%) when a 10 mg dose is given. The mean relative bioavailability of the extended-release tablet is 29% (range: 9% to 66%) compared to an immediate-release capsule administered under fasting conditions. When given orally, fluvastatin reaches peak concentrations (Tmax) in less than one hour. Taking the extended release tablet with a high-fat meal will delay absorption (Tmax = 6 hours) and increase bioavailability by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.35 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% bound to plasma proteins. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces. Both enantiomers of fluvastatin are metabolized in a similar manner. Fluvastatin also undergoes glucuronidation via UGT enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When orally administered, fluvastatin is primarily excreted in the faces ( ~90%) as metabolites, with less than 2% present as unchanged drug. Approximately 5% was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 3 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.8 L/h/kg 107 ± 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg] 87.8 ± 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily] 108 ± 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single] 64.2 ± 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Generally well-tolerated. May cause gastrointestinal upset (diarrhea, nausea, constipation, gas, abdominal pain), myotoxicity (mypothy, myositis, rhabdomyolysis), and hepatotoxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lescol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluvastatin interact? Information: •Drug A: Abatacept •Drug B: Fluvastatin •Severity: MODERATE •Description: The metabolism of Fluvastatin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): To be used as an adjunct to dietary therapy to prevent cardiovascular events. May be used as secondary prevention in patients with coronary heart disease (CHD) to reduce the risk of requiring coronary revascularization procedures, for reducing progression of coronary atherosclerosis in hypercholesterolemic patients with CHD, and for the treatment of primary hypercholesterolemia and mixed dyslidipidemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluvastatin, the first synthetically-derived HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Fluvastatin acts primarily in the liver. It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total and LDL cholesterol. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%) when a 10 mg dose is given. The mean relative bioavailability of the extended-release tablet is 29% (range: 9% to 66%) compared to an immediate-release capsule administered under fasting conditions. When given orally, fluvastatin reaches peak concentrations (Tmax) in less than one hour. Taking the extended release tablet with a high-fat meal will delay absorption (Tmax = 6 hours) and increase bioavailability by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.35 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% bound to plasma proteins. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces. Both enantiomers of fluvastatin are metabolized in a similar manner. Fluvastatin also undergoes glucuronidation via UGT enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When orally administered, fluvastatin is primarily excreted in the faces ( ~90%) as metabolites, with less than 2% present as unchanged drug. Approximately 5% was recovered in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 3 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.8 L/h/kg 107 ± 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg] 87.8 ± 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily] 108 ± 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single] 64.2 ± 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Generally well-tolerated. May cause gastrointestinal upset (diarrhea, nausea, constipation, gas, abdominal pain), myotoxicity (mypothy, myositis, rhabdomyolysis), and hepatotoxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lescol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Fluvoxamine interact?

•Drug A: Abatacept •Drug B: Fluvoxamine •Severity: MODERATE •Description: The metabolism of Fluvoxamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated predominantly for the management of depression and for Obsessive Compulsive Disorder (OCD). Has also been used in the management of bulimia nervosa. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluvoxamine, an aralkylketone-derivative agent, is one of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) that differs structurally from other SSRIs. It is used to treat the depression associated with mood disorders. It is also used on occassion in the treatment of body dysmorphic disorder and anxiety. The antidepressant, antiobsessive-compulsive, and antibulimic actions of Fluvoxamine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. In vitro studies show that Fluvoxamine is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. Moreover, apart from binding to σ1 receptors, fluvoxamine has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT 1A, 5HT 1B, 5HT 2 ), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Furthermore, some studies have demonstrated that the chronic administration of Fluvoxamine was found to downregulate brain norepinephrine receptors (as has been observed with other drugs effective in the treatment of major depressive disorder), while others suggest the opposite. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of fluvoxamine has not been fully determined, but appears to be linked to its inhibition of CNS neuronal uptake of serotonin. Fluvoxamine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT 1A autoreceptors. Studies have also demonstrated that fluvoxamine has virtually no affinity for α 1 - or α 2 -adrenergic, β-adrenergic, muscarinic, dopamine D 2, histamine H 1, GABA-benzodiazepine, opiate, 5-HT 1, or 5-HT 2 receptors, despite having an affinity for binding to σ1 receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed, bioavailability of fluvoxamine maleate is 53%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 25 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~77-80% (plasma protein). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluvoxamine is metabolized extensively by the liver. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Nine metabolites were identified following a 5 mg radio labelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15.6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluvoxamine is a member of antidepressants that possess an increased risk compared to placebo of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages including and and below 24) in short-term studies of major depressive disorder and other psychiatric disorders. Fluvoxamine maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). Side effects include anorexia, constipation, dry mouth, headache, nausea, nervousness, skin rash, sleep problems, somnolence, liver toxicity, mania, increase urination, seizures, sweating increase, tremors, or Tourette's syndrome. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Luvox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluvoxamine is a selective serotonin-reuptake inhibitor used to treat obsessive-compulsive disorder.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fluvoxamine interact? Information: •Drug A: Abatacept •Drug B: Fluvoxamine •Severity: MODERATE •Description: The metabolism of Fluvoxamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated predominantly for the management of depression and for Obsessive Compulsive Disorder (OCD). Has also been used in the management of bulimia nervosa. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fluvoxamine, an aralkylketone-derivative agent, is one of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) that differs structurally from other SSRIs. It is used to treat the depression associated with mood disorders. It is also used on occassion in the treatment of body dysmorphic disorder and anxiety. The antidepressant, antiobsessive-compulsive, and antibulimic actions of Fluvoxamine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. In vitro studies show that Fluvoxamine is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. Moreover, apart from binding to σ1 receptors, fluvoxamine has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT 1A, 5HT 1B, 5HT 2 ), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Furthermore, some studies have demonstrated that the chronic administration of Fluvoxamine was found to downregulate brain norepinephrine receptors (as has been observed with other drugs effective in the treatment of major depressive disorder), while others suggest the opposite. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of fluvoxamine has not been fully determined, but appears to be linked to its inhibition of CNS neuronal uptake of serotonin. Fluvoxamine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT 1A autoreceptors. Studies have also demonstrated that fluvoxamine has virtually no affinity for α 1 - or α 2 -adrenergic, β-adrenergic, muscarinic, dopamine D 2, histamine H 1, GABA-benzodiazepine, opiate, 5-HT 1, or 5-HT 2 receptors, despite having an affinity for binding to σ1 receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed, bioavailability of fluvoxamine maleate is 53%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 25 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~77-80% (plasma protein). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fluvoxamine is metabolized extensively by the liver. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Nine metabolites were identified following a 5 mg radio labelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15.6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Fluvoxamine is a member of antidepressants that possess an increased risk compared to placebo of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages including and and below 24) in short-term studies of major depressive disorder and other psychiatric disorders. Fluvoxamine maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). Side effects include anorexia, constipation, dry mouth, headache, nausea, nervousness, skin rash, sleep problems, somnolence, liver toxicity, mania, increase urination, seizures, sweating increase, tremors, or Tourette's syndrome. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Luvox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fluvoxamine is a selective serotonin-reuptake inhibitor used to treat obsessive-compulsive disorder. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Formoterol interact?

•Drug A: Abatacept •Drug B: Formoterol •Severity: MODERATE •Description: The metabolism of Formoterol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) aclidinium and glycopyrronium, and in combination with the corticosteroid budesonide. For the treatment of asthma, formoterol is available in combination with mometasone furoate for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Formoterol is a relatively selective long-acting agonist of beta 2 -adrenergic receptors, although it does carry some degree of activity at beta 1 and beta 3 receptors. Beta 2 receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta 1 receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta 2 receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta 2 receptors over beta 1 receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C max and AUC 0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C max and AUC 0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding to serum albumin in vitro is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. In vitro studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal clearance of formoterol following inhalation is approximately 157 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 3130 mg/kg. Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bevespi, Breyna, Breztri, Duaklir, Duaklir Genuair, Dulera, Foradil, Oxeze, Perforomist, Symbicort, Zenhale •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Formoterol Formoterolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Formoterol is an inhaled long-acting beta2-adrenergic receptor agonist used as a bronchodilator in the management of asthma and COPD.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Formoterol interact? Information: •Drug A: Abatacept •Drug B: Formoterol •Severity: MODERATE •Description: The metabolism of Formoterol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) aclidinium and glycopyrronium, and in combination with the corticosteroid budesonide. For the treatment of asthma, formoterol is available in combination with mometasone furoate for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Formoterol is a relatively selective long-acting agonist of beta 2 -adrenergic receptors, although it does carry some degree of activity at beta 1 and beta 3 receptors. Beta 2 receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta 1 receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta 2 receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta 2 receptors over beta 1 receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C max and AUC 0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C max and AUC 0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding to serum albumin in vitro is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. In vitro studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Renal clearance of formoterol following inhalation is approximately 157 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 3130 mg/kg. Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bevespi, Breyna, Breztri, Duaklir, Duaklir Genuair, Dulera, Foradil, Oxeze, Perforomist, Symbicort, Zenhale •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Formoterol Formoterolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Formoterol is an inhaled long-acting beta2-adrenergic receptor agonist used as a bronchodilator in the management of asthma and COPD. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Abatacept and Fosaprepitant interact?

•Drug A: Abatacept •Drug B: Fosaprepitant •Severity: MODERATE •Description: The metabolism of Fosaprepitant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fosaprepitant is indicated in adult and pediatric patients ≥6 months of age, in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. It is also indicated for the treatment of delayed nausea and vomiting with initial and repeat courses of moderately emetogenic cancer chemotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. In summary, the active form of fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% + •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 9-13 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Emend, Focinvez •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fosaprepitant is an antiemetic drug used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting caused by chemotherapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fosaprepitant interact? Information: •Drug A: Abatacept •Drug B: Fosaprepitant •Severity: MODERATE •Description: The metabolism of Fosaprepitant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fosaprepitant is indicated in adult and pediatric patients ≥6 months of age, in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. It is also indicated for the treatment of delayed nausea and vomiting with initial and repeat courses of moderately emetogenic cancer chemotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. In summary, the active form of fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% + •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 9-13 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Emend, Focinvez •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fosaprepitant is an antiemetic drug used in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting caused by chemotherapy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Fosphenytoin interact?

•Drug A: Abatacept •Drug B: Fosphenytoin •Severity: MAJOR •Description: The metabolism of Fosphenytoin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fosphenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in adult patients. It can also be substituted, short-term, for oral phenytoin in patients aged two years and older when oral phenytoin administration is not possible. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fosphenytoin is a water-soluble phenytoin prodrug used for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. Each 1.5 mg of fosphenytoin sodium is equivalent to 1.0mg of phenytoin sodium (PE equivalents); care should be taken to calculate the dose required in PE equivalents properly. Serious adverse effects such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and hematopoietic complications may occur and indicate an alternate antiepileptic should be used. Withdrawal of fosphenytoin sodium may precipitate seizures and should be done gradually. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fosphenytoin increases with dose and rate, ranging between 4.3 and 10.8 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fosphenytoin is extensively bound (95-99%) to human plasma proteins, primarily albumin, and displays saturable binding kinetics over a physiologically relevant range of fosphenytoin concentrations. Like fosphenytoin, phenytoin is extensively bound, again mainly to albumin, but can be displaced by fosphenytoin itself. Phenytoin is typically about 88% bound in the absence of fosphenytoin, but this drops to around 60% 0.5-1 hour following fosphenytoin infusion while fosphenytoin is being converted to phenytoin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Phenytoin derived from fosphenytoin administration is excreted in the urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged phenytoin (1%–5% of the administered dose), and essentially no fosphenytoin recovered in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fosphenytoin has a conversion half-life of approximately 15 minutes. The resulting phenytoin has a wide range of mean total half-life values (12 to 28.9 hours), with longer half-life times at higher administered doses. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cerebyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fosfenitoina Fosphenytoin Fosphenytoine Fosphenytoinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fosphenytoin is an antiepileptic agent used for the management of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Fosphenytoin interact? Information: •Drug A: Abatacept •Drug B: Fosphenytoin •Severity: MAJOR •Description: The metabolism of Fosphenytoin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fosphenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in adult patients. It can also be substituted, short-term, for oral phenytoin in patients aged two years and older when oral phenytoin administration is not possible. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fosphenytoin is a water-soluble phenytoin prodrug used for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. Each 1.5 mg of fosphenytoin sodium is equivalent to 1.0mg of phenytoin sodium (PE equivalents); care should be taken to calculate the dose required in PE equivalents properly. Serious adverse effects such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and hematopoietic complications may occur and indicate an alternate antiepileptic should be used. Withdrawal of fosphenytoin sodium may precipitate seizures and should be done gradually. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of fosphenytoin increases with dose and rate, ranging between 4.3 and 10.8 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Fosphenytoin is extensively bound (95-99%) to human plasma proteins, primarily albumin, and displays saturable binding kinetics over a physiologically relevant range of fosphenytoin concentrations. Like fosphenytoin, phenytoin is extensively bound, again mainly to albumin, but can be displaced by fosphenytoin itself. Phenytoin is typically about 88% bound in the absence of fosphenytoin, but this drops to around 60% 0.5-1 hour following fosphenytoin infusion while fosphenytoin is being converted to phenytoin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Phenytoin derived from fosphenytoin administration is excreted in the urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged phenytoin (1%–5% of the administered dose), and essentially no fosphenytoin recovered in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Fosphenytoin has a conversion half-life of approximately 15 minutes. The resulting phenytoin has a wide range of mean total half-life values (12 to 28.9 hours), with longer half-life times at higher administered doses. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cerebyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fosfenitoina Fosphenytoin Fosphenytoine Fosphenytoinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fosphenytoin is an antiepileptic agent used for the management of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Frovatriptan interact?

•Drug A: Abatacept •Drug B: Frovatriptan •Severity: MODERATE •Description: The metabolism of Frovatriptan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the acute treatment of migraine attacks with or without aura in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Frovatriptan is a second generation triptan 5-HT receptor agonist that binds with high affinity for 5-HT 1B and 5-HT 1D receptors. It is structurally distinct from, but pharmacologically related to other selective 5-HT 1B/1D receptor agonists. Frovatriptan has no significant effects on GABA A mediated channel activity and has no significant affinity for benzodiazepine binding sites. Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. Research has shown that migraine can be caused by the swelling of blood vessels around the brain. Frovatriptan eases the pain associated with migraine by narrowing these blood vessels. Frovatriptan has one of the highest affinities for the 5-HT 1B of the second-generation triptan agonists. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT 1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT 1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT 1B receptor agonism. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 4.2 L/kg [males] 3 L/kg [females] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT 1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 26 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 220 mL/min [male receiving IV dose of 0.8 mg] 130 mL/min [Female receiving IV dose of 0.8 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Frova •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Frovatriptan is a 5-HT1B/1D receptor agonist used to treat migraines.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Frovatriptan interact? Information: •Drug A: Abatacept •Drug B: Frovatriptan •Severity: MODERATE •Description: The metabolism of Frovatriptan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the acute treatment of migraine attacks with or without aura in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Frovatriptan is a second generation triptan 5-HT receptor agonist that binds with high affinity for 5-HT 1B and 5-HT 1D receptors. It is structurally distinct from, but pharmacologically related to other selective 5-HT 1B/1D receptor agonists. Frovatriptan has no significant effects on GABA A mediated channel activity and has no significant affinity for benzodiazepine binding sites. Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. Research has shown that migraine can be caused by the swelling of blood vessels around the brain. Frovatriptan eases the pain associated with migraine by narrowing these blood vessels. Frovatriptan has one of the highest affinities for the 5-HT 1B of the second-generation triptan agonists. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT 1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT 1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT 1B receptor agonism. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 4.2 L/kg [males] 3 L/kg [females] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT 1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 26 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 220 mL/min [male receiving IV dose of 0.8 mg] 130 mL/min [Female receiving IV dose of 0.8 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Frova •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Frovatriptan is a 5-HT1B/1D receptor agonist used to treat migraines. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.