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BackgroundThe CURRENT-OASIS-7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin.

ObjectiveTo explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels.

MethodsIn part 1, using a 2x2 factorial design, we randomized patients to clopidogrel 600mg loading dose (LD) followed by 150mgday(-1) for 6days and 75mgday(-1) thereafter, or clopidogrel 300mg LD followed by 75mgday(-1) thereafter, and compared aspirin at 325mg or 81mgday(-1). In part 2, patients were given a 600-mg clopidogrel LD, and were randomly allocated to aspirin 325mg or 81mgday(-1). We combine the data from the two parts. Blood samples were collected 1h after administration of the study drug.

ResultsWe randomized 302 patients (mean age 60.49.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81mg (geometric mean, 12.70ngmL(-1); 95% CI, 10.96-14.72 ngmL(-1); and geometric mean, 12.55ngmL(-1); 95% CI, 10.80-14.58ngmL(-1); P=0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss-of-function (LOF) carriers compared with non-carriers (10.72ngmL(-1); 95% CI, 8.83-13.01ngmL(-1); and 15.21ngmL(-1); 95% CI, 13.30-17.40ngmL(-1), respectively; P=0.003) whereas levels in gain of function carriers and non-carriers were similar (13.31ngmL(-1); 95% CI, 11.53-15.35ngmL(-1); and 14.07ngmL(-1); 95% CI, 11.74-16.87ngmL(-1), respectively; P=0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels.

ConclusionAspirin dose does not predict clopidogrel AM levels 1h post-LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status.