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

• Published in: Journal of the American College of Cardiology 2013-02, Vol.61 (8), p.872-879
• Main Authors: Frelinger, Andrew L., PhD, Bhatt, Deepak L., MD, MPH, Lee, Ronald D., PhD, Mulford, Darcy J., PhD, Wu, Jingtao, PhD, Nudurupati, Sai, PhD, Nigam, Anu, MS, Lampa, Michael, BS, Brooks, Julie K., MS, Barnard, Marc R., MS, Michelson, Alan D., MD
• Format: Article
• Language: English
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles - administration & dosage; 2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics; Acute coronary syndromes; Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; Aryldialkylphosphatase - genetics; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Blood Coagulation - drug effects; Body mass index; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular Diseases - blood; Cardiovascular Diseases - etiology; Cardiovascular Diseases - prevention & control; Cardiovascular Diseases - psychology; Confounding Factors (Epidemiology); Cross-Over Studies; Cytochrome; Cytochrome P-450 CYP2C19; Demographics; Drug dosages; Drug Interactions; Drug Monitoring - methods; Drug therapy; Drug Therapy, Combination; drugs; Female; Genotype & phenotype; Humans; Internal Medicine; Male; Medical sciences; Middle Aged; Nutrition research; Patient Compliance; pharmacokinetics; Platelet Aggregation - drug effects; Platelet Aggregation - genetics; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Function Tests - methods; platelets; Polymorphism, Genetic; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - pharmacokinetics; receptors; risk factors; Smoking - metabolism; Studies; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacokinetics; Tobacco, tobacco smoking; Toxicology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2012.11.040

Objectives This study sought 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. Background Platelet inhibition by clopidogrel is highly variable. Patients with reduced inhibition have increased risk for major adverse cardiovascular events. Identification of factors contributing to clopidogrel's variable response is needed to improve platelet inhibition and reduce risk for cardiovascular events. Methods Healthy subjects (n = 160; ages 20 to 53 years; homozygous CYP2C19 extensive metabolizer genotype; no nicotine for 6 weeks, prescription drugs for 4 weeks, over-the-counter drugs for 2 weeks, and no caffeine or alcohol for 72 h; confined; restricted diet) received clopidogrel 75 mg/day for 9 days, at which time clopidogrel pharmacokinetic and pharmacodynamic endpoints were measured. Results At steady-state, clopidogrel active metabolite (clopidogrelAM ) pharmacokinetics varied widely between subjects (coefficients of variation [CVs] 33.8% and 40.2% for clopidogrelAM area under the time-concentration curve and peak plasma concentration, respectively). On-treatment vasodilator stimulated phosphoprotein P2Y12 platelet reactivity index (PRI), maximal platelet aggregation (MPA) to adenosine phosphate, and VerifyNow P2Y12 platelet response units (PRU) also varied widely (CVs 32% to 53%). All identified factors together accounted for only 18% of intersubject variation in pharmacokinetic parameters and 32% to 64% of intersubject variation in PRI, MPA, and PRU. High on-treatment platelet reactivity was present in 45% of subjects. Conclusions Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms ( CYP2C19 , CYP3A5 , ABCB1 , PON1 ), noncompliance, 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. (A Study of the Effects of Multiple Doses of Dexiansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants: NCT00942175 )