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European Heart Journal Advance Access originally published online on May 9, 2009
European Heart Journal 2009 30(14):1744-1752; doi:10.1093/eurheartj/ehp157
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease

Christoph Varenhorst1,*, Stefan James1, David Erlinge2, John T. Brandt3, Oscar Ö. Braun2, Michael Man3, Agneta Siegbahn4, Joseph Walker5, Lars Wallentin1, Kenneth J. Winters3 and Sandra L. Close3

1 Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
2 Department of Cardiology, Lund University, Lund, Sweden
3 Eli Lilly and Company, Indianapolis, IN, USA
4 Coagulation Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
5 Daiichi Sankyo, Inc., Parsippany, NJ, USA

Received 26 September 2008; revised 12 March 2009; accepted 19 March 2009; online publish-ahead-of-print 9 May 2009.

* Corresponding author. Tel: +46 18 611 95 00, Fax: +46 18 50 66 38, Email: christoph.varenhorst{at}ucr.uu.se

Aims: The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.

Methods and results: Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNowTM P2Y12 were measured predose, 2, and 24 ± 4 h post-LD and predose during the MD period on Day 14 ± 3 and Day 29 ± 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNowTM P2Y12 reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses.

Conclusion: Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y12 inhibition, but has no significant influence on the response to prasugrel.

Key Words: Clopidogrel • Prasugrel • Cytochrome P450 enzymes • CYP2C19 • Pharmacogenetics


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