Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. (7th April 2014)

• Record Type: Journal Article
• Authors: Horenstein, Richard B.; Madabushi, Rajnikanth; Zineh, Issam; Yerges‐Armstrong, Laura M.; Peer, Cody J.; Schuck, Robert N.; Figg, William Douglas; Shuldiner, Alan R.; Pacanowski, Michael A.
• Is Part Of: Journal of clinical pharmacology. Volume 54:Number 8(2014:Aug.)
• Page Start: 865
• Page End: 873
• Publication Date: 2014-04-07
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.293
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph293-sec-0001" sec-type="section"> <p>Carriers of two copies of the loss‐of‐function <italic>CYP2C19*2</italic> 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 <italic>CYP2C19 * 2</italic> 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 (<italic>P</italic> &lt; .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.</p> </sec> </abstract>