The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease

Paul A. Gurbel, Thomas O. Bergmeijer, Udaya S. Tantry, Jurrien M. Ten Berg, Dominick J. Angiolillo, Stefan James, Tomas L. Lindahl, Peter Svensson, Joseph A. Jakubowski, Patricia B. Brown, Suman Duvvuru, Scott Sundseth, Joseph R. Walker, David Small, Brian A. Moser, Kenneth J. Winters, David Erlinge

Research output: Contribution to journalArticle

Abstract

CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiv ing clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VNPRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

Original languageEnglish (US)
Pages (from-to)589-597
Number of pages9
JournalThrombosis and Haemostasis
Volume112
Issue number3
DOIs
StatePublished - Jan 1 2014

Keywords

  • CYP2C19
  • Clopidogrel
  • Coronary artery disease
  • Platelet reactivity
  • Prasugrel

ASJC Scopus subject areas

  • Hematology

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    Gurbel, P. A., Bergmeijer, T. O., Tantry, U. S., Ten Berg, J. M., Angiolillo, D. J., James, S., Lindahl, T. L., Svensson, P., Jakubowski, J. A., Brown, P. B., Duvvuru, S., Sundseth, S., Walker, J. R., Small, D., Moser, B. A., Winters, K. J., & Erlinge, D. (2014). The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease. Thrombosis and Haemostasis, 112(3), 589-597. https://doi.org/10.1160/TH13-10-0891