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

Study Questions:

Platelet inhibition by clopidogrel is highly variable. Do genetic, drug, dietary, compliance, and lifestyle factors affecting clopidogrel absorption and metabolism fully account for the variability in clopidogrel pharmacokinetics and pharmacodynamics?

Methods:

Healthy subjects (n = 160; ages 20-53 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 hours; 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 (PRUs) also varied widely (CVs 32%-53%). All identified factors together accounted for only 18% of intersubject variation in pharmacokinetic parameters and 32%-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), clinical variables, and pretreatment platelet hyper-reactivity. As yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events.

Perspective:

This elegant study demonstrates the complexity of identifying variables associated with drug response, particularly one in which genetic polymorphisms play a role. As the authors concluded, if found, the sources of the remaining variations in platelet response to clopidogrel may be future therapeutic targets.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Prevention, Diet, Smoking

Keywords: Nicotine, Microfilament Proteins, Platelet Aggregation Inhibitors, Platelet Function Tests, Nonprescription Drugs, Angioplasty, Proton Pump Inhibitors, Smoking, Polymorphism, Genetic, Biological Markers, Troponin I, Prescription Drugs, Cardiology, Phosphoproteins, Diet, Cell Adhesion Molecules, Cytochrome P-450 CYP3A


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