Abstract 9871: Enhanced Active Metabolite Generation and Platelet Inhibition With Prasugrel Compared to Clopidogrel Regardless of Genotype in Thienopyridine Metabolic Pathways
Background: Clopidogrel (Clop) response is modulated by genetic polymorphisms. In particular, the CYP2C19*2 allele has been associated with impaired response, while conflicting results have been reported for CYP2C19*17, ABCB1 and PON1 genotypes. We assessed the impact of CYP2C19, PON1 and ABCB1 polymorphisms on Clop and prasugrel (Pras) pharmacodynamic (PD) response and pharmacokinetic (PK) profile.
Methods: Aspirin-treated patients (n=194) with coronary artery disease enrolled in two independent, prospective, randomized, multicenter studies comparing Clop (75 mg) and Pras (10 mg) were genotyped and classified according to standard definitions of predicted CYP2C19 metabolizer phenotype (ultra metabolizers (UM) = *17 carriers; reduced metabolizers (RM) = *2 carriers). PD assessments were made using LTA, VerifyNow P2Y12 and VASP-PRI (platelet reactivity index) after 14 days of maintenance dosing. PK parameters of active metabolite (AM) exposure of both Clop and Pras were calculated in a cohort of 98 patients.
Results: For Clop, genetic variants in CYP2C19, but not ABCB1 or PON1, affected the PK and PD. For Pras, none of the measured genetic variants affected PK or PD. Compared with Clop, platelet inhibition with Pras was greater even in CYP2C19 UM phenotype (figure). Pras generated more AM and achieved greater platelet inhibition than Clop irrespective of CYP2C19, ABCB1 and PON1 polymorphisms.
Conclusion: Pras generated higher levels of AM and achieved greater platelet inhibition than Clop in all CYP2C19 genotypes. Neither ABCB1 nor PON1 genetic variation affected Pras or Clop PD or PK response.
- © 2012 by American Heart Association, Inc.