Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel

TLDR

Cytochrome P450 enzymes convert clopidogrel and prasugrel into active metabolites, and reduced‑function CYP2C19 alleles in clopidogrel users lower active metabolite levels, impair platelet inhibition, and increase cardiovascular events. The study aimed to determine whether CYP genetic variants influence prasugrel pharmacokinetics, platelet inhibition, and cardiovascular outcomes. The authors assessed the impact of CYP variants on prasugrel metabolite levels and platelet inhibition in 238 healthy volunteers and evaluated their association with cardiovascular events in 1466 acute coronary syndrome patients from the TRITON‑TIMI 38 trial. In both healthy volunteers and acute coronary syndrome patients, common functional CYP variants did not alter prasugrel metabolite concentrations, platelet inhibition, or cardiovascular event rates, unlike the effects seen with clopidogrel.

Abstract

Background— Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. Methods and Results— The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested ( CYP2C19 , CYP2C9 , CYP2B6 , CYP3A5 , and CYP1A2 ). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Conclusions— Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.