Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers

Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19*2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the*1/*1 extensive (EM),*1/*2 intermediate (IM), and*2/*2 poor metabolizer genotypes each received 75mg, 150 mg, and 300mg each for 8 days. In each period, maximal platelet aggregation 4hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P<.05 for all). At day 8, PMs needed 300mg daily and IMs needed 150mg daily to attain a similar MPA4 as EMs on the 75mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300mg daily to achieve active metabolite concentrations that were similar to EMs on 75mg (AUC 37.7 and 33.5ngh/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism.