Faculty Collaboration Database

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways. Thromb Haemost 2013 Dec;110(6):1223-31

Date

09/07/2013

Pubmed ID

24009042

DOI

10.1160/TH13-03-0263

Scopus ID

2-s2.0-84888407930 (requires institutional sign-in at Scopus site)   15 Citations

Abstract

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.

Author List

Braun OÖ, Angiolillo DJ, Ferreiro JL, Jakubowski JA, Winters KJ, Effron MB, Duvvuru S, Costigan TM, Sundseth S, Walker JR, Saucedo JF, Kleiman NS, Varenhorst C

Author

Jorge Saucedo MD Chief, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Alleles
Aryl Hydrocarbon Hydroxylases
Aryldialkylphosphatase
Biotransformation
Blood Platelets
Cell Adhesion Molecules
Cells, Cultured
Coronary Artery Disease
Cytochrome P-450 CYP2C19
Female
Humans
Male
Microfilament Proteins
Middle Aged
Phosphoproteins
Piperazines
Platelet Activation
Polymorphism, Genetic
Prasugrel Hydrochloride
Prospective Studies
Pyridines
Receptors, Purinergic P2Y12
Thiophenes
Ticlopidine