Clopidogrel and the concept of high-risk pharmacokinetics.

Four large trials, reported in the last several weeks, have identified loss-of-function alleles in the gene encoding cytochrome P450 2C19 (CYP2C19) as important risk factors predicting apparent failure of clopidogrel efficacy.1–4 Previous studies have shown that clopidogrel is a prodrug that requires bioactivation,5 mediated in part by CYP2C19, to achieve its antiplatelet efficacy.6 All 4 trials built on this knowledge and studied the effects of CYP2C19 variants on coronary events (including death, myocardial infarction, and in-stent thrombosis) in patients receiving clopidogrel. Hazard ratios for a single CYP2C19 variant allele ranged from 1.5 to 4, depending on the end point and the specific population. We describe here how this apparently surprising outcome could be anticipated from first principles in clinical pharmacology. We then discuss how considering this result within the context of a contemporary understanding of clinical pharmacokinetics and pharmacogenetics raises new hypotheses that require further testing.