What is the clinical evidence from this study?

Study design: Other. Population: Healthy subjects (n=160). Intervention: Clopidogrel. Primary outcome: Clopidogrel active metabolite pharmacokinetics and pharmacodynamics (PRI, MPA, PRU).

June 3, 2026

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

Key Result

Clopidogrel pharmacokinetics and pharmacodynamics varied widely (CVs 32% to 53%) despite rigorous control of known genetic, dietary, and lifestyle factors, with 45% showing high platelet reactivity.

Key Points

This research aims to investigate the variability in clopidogrel pharmacokinetics and pharmacodynamics despite controlling for various influencing factors.
Controlled for polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, and co-medications.
Assessed the impact of factors like proton pump inhibitors on clopidogrel responses.
Evaluated pre-existent variability in platelet function.
Clopidogrel pharmacokinetics demonstrated significant inter-individual variability despite controlling for tested factors.
Pharmacodynamic responses were inconsistent among individuals, suggesting unexplained variability in medication efficacy.
Factors such as diet and co-medications influenced pharmacokinetic and pharmacodynamic outcomes.

Structured PICO

Does clopidogrel 75 mg/day produce variable pharmacokinetics and pharmacodynamics in healthy subjects despite strict control of known genetic, dietary, and lifestyle factors?

Population

160 healthy subjects aged 20 to 53 years with homozygous CYP2C19 extensive metabolizer genotype, strictly controlled for diet, smoking, and co-medications, who received clopidogrel for 9 days.

Intervention

Clopidogrel 75 mg/day for 9 days

Outcome

Clopidogrel active metabolite pharmacokinetics (area under the time-concentration curve and peak plasma concentration) and pharmacodynamics (vasodilator stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation, and VerifyNow P2Y12 platelet response units) at steady-state (day 9)surrogate

Clopidogrel pharmacokinetics and pharmacodynamics exhibit wide interindividual variability that cannot be fully explained by known genetic, dietary, or lifestyle factors, leaving a significant proportion of patients with high on-treatment platelet reactivity.

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 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).

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