Clopidogrel and the Concept of High-Risk Pharmacokinetics

D. M. Roden, C. M. Stein
2009 Circulation  
F our 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
more » ... ry 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. Anticipating This Result: The Concept of High-Risk Pharmacokinetics 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 bioactivation that relies on a single pathway will display highly variable clinical effects if that pathway is inhibited or absent on a genetic basis. This is the issue with clopidogrel and a number of other drugs described here. Variable Bioactivation of Other Prodrugs Approximately 7% of the European American and African American populations lack functional alleles for another P450, CYP2D6. 9 Codeine is bioactivated to its active metabolite (morphine) by this enzyme, and CYP2D6-poor metabolizers display decreased analgesic opioid effects of the drug. 10 Tamoxifen is bioactivated by a number of pathways, including CYP2D6, 11 and preliminary analyses of outcomes during tamoxifen therapy as a function of CYP2D6 genotype support the idea that poor metabolizers have an increased incidence of recurrent breast cancer during tamoxifen therapy. 12-14 High-Risk Pharmacokinetics and Drug Elimination A second high-risk situation is the administration of a drug that has the potential to cause serious toxicity at high concentrations and whose elimination depends on a single pathway. In this case, perturbation of that pathway, by genetic factors or by interactions, can lead to marked increases in drug concentrations (because alternate pathways for drug elimination are not present) and thus drug toxicity (see the Figure) . Warfarin is bioinactivated by CYP2C9-mediated metabolism. Common variants in this enzyme lead to a reduction of function (CYP2C9*2) or near-complete reduction of function (CYP2C9*3). Rare individuals who are homozygous for the loss-of-function allele (*3/*3, Յ1% of a white population) display striking reductions in warfarin dose requirement and may be at increased risk for complications during therapy. 15, 16 It is now apparent that warfarin dose requirements reflect variation in both CYP2C9 and VKORC1, which encodes a protein in the vitamin K receptor complex that is the target of the warfarin drug action. Because there is such a narrow margin between the dosages required for efficacy and those producing toxicity for this drug, adjustment of dose in the broad population exposed to the drug according to genotype, not simply identifying *3/*3 homozygotes, may be a preferred approach. 17 Large trials testing this idea are now in the planning phase. 18 Some drugs are markedly affected by genetic variation in metabolism, but because a wide range of concentrations is well tolerated, the clinical consequences are minor. Metoprolol and timolol undergo CYP2D6-mediated bioinactivation. Toxicity is not a problem in poor metabolizers, however, because marked increases in ␤-blocker concentrations do not result in severe adverse effects; some data suggest that metoprolol cardioselectivity may be lost in poor metabolizers. 19
doi:10.1161/circulationaha.109.865907 pmid:19398674 fatcat:qg73lofppfarjf3lvey7iz5edm