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

Authors

  • Richard B. Horenstein MD,

    1. Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
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  • Rajnikanth Madabushi PhD,

    1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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  • Issam Zineh PharmD, MPH,

    1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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  • Laura M. Yerges-Armstrong PhD,

    1. Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
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  • Cody J. Peer PhD,

    1. Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD, USA
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  • Robert N. Schuck PharmD, PhD,

    1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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  • William Douglas Figg PharmD,

    1. Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD, USA
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  • Alan R. Shuldiner MD,

    1. Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
    2. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD, USA
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  • Michael A. Pacanowski PharmD, MPH

    Corresponding author
    1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
    • Corresponding Author:

      Michael A. Pacanowski, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, White Oak Building 51, Room 3112, HFD870, Silver Spring, MD 20993-0002, USA

      Email: michael.pacanowski@fda.hhs.gov

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  • Disclaimer: The opinions expressed in the article are those of the authors. No official FDA or NIH policy or endorsement is intended nor should be inferred.
  • Clinical Trial Registration: http://www.clinicaltrials.gov; NCT01341600.
  • Published 2014. This article is a U.S. Government work and is in the public domain in the USA

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.

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