Causes of Variability in Response to Clopidogrel Remain Unknown

Multiple mechanisms, including diet, smoking, genetic polymorphisms, compliance and drug-drug interactions, have been proposed as factors that affect clopidogrel pharmacokinetics and pharmacodynamics.
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However, according to a study published on Jan. 16 in the Journal of the American College of Cardiology, none of these factors can fully account for the variability in platelet inhibition observed among patients.

The study enrolled 160 healthy subjects without any known risk factors for suboptimal platelet inhibition. All study participants met the following criteria: 18-55 years of age; homozygous CYP2C19 extensive metabolizer genotype; body mass index between 18 and 30 kg/m2; free of nicotine for six weeks, prescription drugs for four weeks, over-the-counter drugs for two weeks, and caffeine and alcohol for 72 hours. Study participants were confined to a clinical research unit for 10 consecutive days, received standardized meals and snacks, fluid consumption was controlled, and no rigorous exercise was allowed. Clopidogrel 75 mg was administered for nine consecutive days.

Despite these controls, the authors reported wide variability in pharmacokinetics and pharmacodynamics among study participants. All factors combined accounted for only 18 percent of variability in pharmacokinetic parameters, and only 32 percent to 64 percent of variation in the P2Y12 platelet reactivity index among participants.

The authors concluded that clopidogrel pharmacokinetics and pharmacodynamics are variable despite rigorous control of lifestyle and compliance issues, polymorphisms, co-medications and other factors affecting clopidogrel metabolism.

“Sources of remaining variations are unclear, but they may be future therapeutic targets, given that patients with high on-treatment platelet reactivity are at increased risk of major adverse cardiovascular events,” they added.

Keywords: Nicotine, Platelet Aggregation Inhibitors, Nonprescription Drugs, Ticlopidine, Blood Platelets, Risk Factors, Smoking, Drug Interactions, Caffeine, Polymorphism, Genetic, Body Mass Index, Prescription Drugs, Diet, Genotype, United States

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