Clopidogrel in CYP2C19 poor metabolizers: Four-fold dose increase may be needed
Clopidogrel is an antiplatelet agent that is bioactivated through a two-step process involving the polymorphic CYP2C19 enzyme. CYP2C19 genotype can be used to predict clopidogrel response, particularly in patients undergoing percutaneous coronary intervention (PCI). Although increasing the clopidogrel dose in patients who are CYP2C19 poor or intermediate metabolizers is a logical strategy to overcome a decreased response, the optimal dosing strategy needed to achieve antiplatelet response in these patients has not been determined.
Horenstein and colleagues conducted a prospective, open-label, multidose crossover study in 18 healthy, white, Amish men and women (mean age 42 years). Participants were stratified by genotype, with 6 patients in each in metabolizer group: *1/*1 (extensive), *1/*2 (intermediate), and *2/*2 (poor). All patients received clopidogrel 75 mg, 150 mg, and 300 mg daily in succession for 8 days each. Investigators examined the difference in maximal platelet aggregation 4 hours post-dose on day 8 of each dosing period between the 75 mg doses and higher doses.
The 4-hour maximum platelet aggregation and area under the curve differed among genotype groups (P < 0.05 for all). After 8 days at each dose, poor and intermediate metabolizers needed 300 mg and 150 mg per day, respectively, to achieve maximum platelet aggregation similar to that of extensive metabolizers taking 75 mg daily. Additionally, poor metabolizers required a dose of 300 mg daily to reach active metabolite concentrations similar to extensive metabolizers who received 75 mg daily. Active metabolite exposure correlated with antiplatelet response in each dosing period.
Study results are significant in that they demonstrate that quadrupling the clopidogrel dose in CYP2C19 poor metabolizers overcomes the diminished antiplatelet response with standard dosing in these patients. The 2013 Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19-guided clopidogrel dosing state that data are insufficient to recommend increasing the clopidogrel dose in acute coronary syndrome patients who have undergone PCI based on genotype alone. Guideline authors noted, however, that many of the trials that have examined alternative dosing strategies to date have only doubled the clopidogrel maintenance dose.
Findings of the current trial also have important implications for interpreting future study results in this area. “Thus based on our findings and those of Mega et al., the 150 mg dose that is being studied in ongoing genotype-guided outcomes trials, may not be adequate to overcome reduced CYP2C19 metabolism, particularly in [poor metabolizers],” authors of the current study wrote.
Horenstein RB et al. Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. J Clin Pharmacol. 2014;54:865–73.