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Thromb Haemost 2013; 110(06): 1223-1231
DOI: 10.1160/TH13-03-0263
Platelets and Blood Cells
Schattauer GmbH

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways

Oscar Ö. Braun
1   Department of Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
,
Dominick J. Angiolillo
2   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Jose L. Ferreiro
3   Heart Diseases Institute, Hospital Universitari de Bellvitge – IDIBELL, University of Barcelona, Barcelona, Spain
,
Joseph A. Jakubowski
4   Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
,
Kenneth J. Winters
4   Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
,
Mark B. Effron
4   Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
,
Suman Duvvuru
4   Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
,
Timothy M. Costigan
4   Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
,
Scott S. Sundseth
5   Cabernet Pharmaceuticals, Inc., Once Science Drive, Durham, North Carolina, USA
,
Joseph R. Walker
6   Daiichi Sankyo, Inc., Edison, New Jersey, USA
,
Jorge F. Saucedo
7   Division of Cardiology, North-Shore University HealthSystem, Evanston, Illinois, USA
,
Neal S. Kleiman
8   Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA
,
Christoph Varenhorst
9   Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Science Park, Uppsala, Sweden
› Author Affiliations
Further Information

Publication History

Received: 29 March 2013

Accepted after major revision: 09 August 2013

Publication Date:
30 November 2017 (online)

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Summary

Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Keywords

Clopidogrel - prasugrel - CYP2C19 - PON1 - ABCB1 - platelet function
 

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