Clopidogrel Pharmacokinetics and Pharmacodynamics Vary Widely Despite Exclusion or Control of Polymorphisms (CYP2C19, ABCB1, PON1), Noncompliance, Diet, Smoking, Co-Medications (Including Proton Pump Inhibitors), and Pre-Existent Variability in Platelet Function
| Autor: | Sai Nudurupati, Andrew L. Frelinger, Julie K. Brooks, Jingtao Wu, Ronald D. Lee, Michael Lampa, Anu Nigam, Marc R. Barnard, Darcy Mulford, Deepak L. Bhatt, Alan D. Michelson |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Platelet Aggregation receptors Pharmacology Biochemistry 2-Pyridinylmethylsulfinylbenzimidazoles drugs Esomeprazole P2Y12 risk factors Data monitoring committee Medicine Drug Interactions Platelet Omeprazole Cross-Over Studies Smoking Confounding Factors Epidemiologic Hematology Middle Aged Clopidogrel Cardiovascular Diseases Area Under Curve Anesthesia platelets Drug Therapy Combination Female Aryl Hydrocarbon Hydroxylases Drug Monitoring Cardiology and Cardiovascular Medicine pharmacokinetics medicine.drug Adult medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Ticlopidine Platelet Function Tests Immunology CYP2C19 Pharmacokinetics Internal medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Medical prescription Blood Coagulation Polymorphism Genetic Aryldialkylphosphatase Surrogate endpoint business.industry Proton Pump Inhibitors Cell Biology Cytochrome P-450 CYP2C19 Clinical trial Clinical research Pharmacodynamics Patient Compliance business Platelet Aggregation Inhibitors |
| Zdroj: | Journal of the American College of Cardiology. 61:872-879 |
| ISSN: | 0735-1097 |
| Popis: | Abstract 4356 Background: Platelet inhibition by clopidogrel is highly variable. Patients with reduced inhibition have increased risk for major adverse cardiovascular events. The aim of this study was to determine whether known genetic, drug, dietary, compliance and lifestyle factors affecting clopidogrel absorption and metabolism fully account for the variability in clopidogrel pharmacokinetics and pharmacodynamics. Methods and Results: Healthy subjects (n=160; age 20–53; homozygous CYP2C19 extensive metabolizer genotype; no nicotine 6 weeks, prescription drugs 4 weeks, over-the-counter drugs 2 weeks, caffeine and alcohol 72 hours; confined; restricted diet) received clopidogrel 75 mg daily for 9 days. At steady-state, clopidogrel active metabolite (clopidogrelAM) pharmacokinetics varied widely between subjects (CVs 33.8% and 40.2% for clopidogrelAM AUCt and Cmax, respectively). On-treatment pharmacodynamic endpoints VASP P2Y12 platelet reactivity index (PRI), maximal platelet aggregation (MPA) to ADP, and VerifyNow P2Y12 platelet response units (PRU) also varied widely (CVs 32 – 53%). All identified factors together accounted for only 18% of inter-subject variation in pharmacokinetic parameters and 32 – 64% of inter-subject variation in PRI, MPA, and PRU. High on-treatment platelet reactivity was present in 45% of healthy, homozygous CYP2C19 extensive metabolizer subjects, free of nicotine, alcohol, and co-medications, with witnessed clopidogrel 75 mg/d treatment for 9 days. Conclusions: Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms (CYP2C19, CYP3A5, ABCB1, PON1), non-compliance, co-medications, diet, smoking, alcohol, demographics, and pre-treatment platelet hyperreactivity. Thus, as yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events. Disclosures: Frelinger: Takeda Pharmaceuticals: Research Funding; GLSynthesis: Research Funding. Bhatt:Medscape Cardiology: Membership on an entity's Board of Directors or advisory committees; Boston VA Research Institute: Membership on an entity's Board of Directors or advisory committees; Society of Chest Pain Centers: Membership on an entity's Board of Directors or advisory committees; American Heart Association Get With The Guidelines Science Subcommittee: Chair, Chair Other; American College of Cardiology: Editor, Clinical Trials, Cardiosource Other; Duke Clinical Research Institute: clinical trial steering committees, clinical trial steering committees Other; Slack Publications: Chief Medical Editor, Cardiology Today Intervention Other; WebMD: CME steering committees, CME steering committees Other; Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company: Research Funding; PLx Pharma, Takeda: unfunded research Other. Lee:Takeda Global Research & Development Center, Inc: Employment. Mulford:Takeda Global Research & Development Center, Inc: Employment. Wu:Takeda Global Research & Development Center, Inc: Employment. Nudurupati:Takeda Global Research & Development Center, Inc: Employment. Michelson:Eli Lilly: Data monitoring committee and idependent external monitor of clinical trials, Research Funding; Takeda: Research Funding; Oxygen Biotherapeutics: Research Funding; Alexion: Research Funding; Omthera: Research Funding. |
| Databáze: | OpenAIRE |
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