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
Abstract
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 (clopidogrel(AM)) pharmacokinetics varied widely between subjects (coefficients of variation [CVs] 33.8% and 40.2% for clopidogrel(AM) area under the time-concentration curve and peak plasma concentration, respectively). On-treatment vasodilator stimulated phosphoprotein P2Y(12) 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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 160 participants or records.
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