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

Richard B Horenstein, Rajnikanth Madabushi, Issam Zineh, Laura M Yerges-Armstrong, Cody J Peer, Robert N Schuck, William Douglas Figg, Alan R Shuldiner, Michael A Pacanowski, Richard B Horenstein, Rajnikanth Madabushi, Issam Zineh, Laura M Yerges-Armstrong, Cody J Peer, Robert N Schuck, William Douglas Figg, Alan R Shuldiner, Michael A Pacanowski

Abstract

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 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P < .05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism.

Keywords: CYP2C19; clopidogrel; pharmacogenomics; pharmacokinetics.

© 2014, The American College of Clinical Pharmacology.

Figures

Figure 1. Pharmacodynamic response to increasing doses…
Figure 1. Pharmacodynamic response to increasing doses of clopidogrel in CYP2C19 EMs, IMs, and PMs
MPA4 (left) and IPA4 (right) are shown by dosing period and CYP2C19 genotype. Boxplots represent median and interquartile range. Connecting lines represent group means.
Figure 2. Pharmacokinetics of clopidogrel active metabolite…
Figure 2. Pharmacokinetics of clopidogrel active metabolite with increasing doses of clopidogrel in EMs, IMs, and PMs
Clopidogrel active metabolite Cmax (left) and AUC0-4 (right) are shown by dosing period and CYP2C19 genotype. Boxplots represent median and interquartile range. Connecting lines represent group means.
Figure 3. Exposure-response relationship for clopidogrel active…
Figure 3. Exposure-response relationship for clopidogrel active metabolite
MPA4 is plotted by AUC0-4 according to CYP2C19 genotype and clopidogrel dose level. The line of best fit is plotted and the equation and R2 value are provided.

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