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.In an era of increasing attention on multiple genetic variants as mediators of variability in drug action (pharmacogenomics), it is a bit of a surprise to see such a spectacular effect of a single set of variants on clinically important outcomes for a very widely used drug. However, the new findings with clopidogrel are entirely consistent with a set of clinical pharmacokinetic findings that now extend back decades and define the concept of high-risk pharmacokinetics ,7,8 a risk of serious drug toxicity when drug concentrations depend on variable activity of a single metabolic pathway.The processes of absorption, distribution, metabolism, and excretion rely on specific proteins that metabolize drugs and move them into and out of cells. Although the activities of these processes vary among individuals, we now understand that genetic variation can result in near-complete absence of enzymatic activity in some individuals. It follows that drugs with a …