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

Abstract

AimsThe 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 resultsNinety-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 VerifyNow™ 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 VerifyNow™ 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.ConclusionVariation 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.

Anti-platelet Therapy Resistance – Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities

“…Common polymorphisms in the CYP2C19 gene, seen in 30-55% of the population depending on the genetic background and ethnic group, significantly diminish response to clopidogrel [50,51]. Clinical studies confirmed the impact of CYP2C19 genotype on clinical outcomes [50,52].…”

The role of genetic factors in clopidogrel antiplatelet therapy

“…A significantly lower level of the active metabolite of clopidogrel was found in patients carrying the deficient CYP2C19 gene allele as compared to patients with normal genotype. Such relations were not detected for prasugrel [21].…”

Cardiovascular pharmacogenetics

“…Prasugrel overcame the form of clopidogrel resistance mediated by the CYP2C19*2 variant (Wiviott et al, 2007) which is especially important given that many individuals (25% of Whites, 30% of Africans, and up to 50% of Asians) carry this genetic variant (Mega et al, 2009b). In a randomised study involving 98 aspirin-treated patients with coronary artery disease, it was found that prasugrel efficacy is not dependent on CYP2C19 metabolism when compared to clopidogrel (Varenhorst et al, 2009). Prasugrel also appears to be more effective than clopidogrel in reducing adenosine diphosphate mediated platelet aggregation (Sugidachi et al, 2000;Varenhorst et al, 2009).…”

“…In a randomised study involving 98 aspirin-treated patients with coronary artery disease, it was found that prasugrel efficacy is not dependent on CYP2C19 metabolism when compared to clopidogrel (Varenhorst et al, 2009). Prasugrel also appears to be more effective than clopidogrel in reducing adenosine diphosphate mediated platelet aggregation (Sugidachi et al, 2000;Varenhorst et al, 2009). Genetic testing for CYP2C19*2 could assist clinicians in the choice of therapy: carriers of CYP2C19*2 who are unlikely to benefit from clopidogrel should avoid exposure to the drug and be given prasugrel as a safer and more effective alternative.…”