The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response

Abstract

Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).

Influence of Genetic Polymorphisms on the Effect of High- and Standard-Dose Clopidogrel After Percutaneous Coronary Intervention

“…Data regarding the effect of the ABCB1 3435 C¡T polymorphism on clopidogrel pharmacodynamics is limited and inconsistent (14,17,35,36). The impact of the ABCB1 genotype on clinical outcomes after PCI has also been discordant between studies (17,18,25).…”

Implications of Inter-Individual Differences in Clopidogrel Metabolism, with Focus on Pharmacogenetics

“…The relationship between CYP2C19 genotype and platelet response to clopidogrel has been confirmed in a number of studies in patients (both Caucasian and Asian) with acute coronary syndrome or undergoing PCI [19,20,21,22,23,24,25]. In only one of them, the plasma levels of the active metabolite of clopidogrel were analysed [25].…”

“…However, no impact of the CYP2C19*17 allele on ADP-induced platelet aggregation was observed. In one further study, CYP2C19*17 carriers unexpectedly had decreased platelet inhibition (measured by Verifynow P2Y12 analyser), similar to that in carriers of defect alleles, compared to CYP2C19*1*1 carriers 2 hours after a 600 mg dose of clopidogrel [22]. Unfortunately, no plasma concentration data were available in the latter studies.…”

“…However, three later studies failed to repeat this association [18,20,24]. The impact of CYP3A5 polymorphisms on platelet aggregation in response to clopidogrel has been studied in healthy volunteers and patients, with no difference in the antiplatelet activity being found between carriers of CYP3A5*1 (required for expression of the enzyme) and those with CYP3A5*3*3 genotype (with no CYP3A5 expression) [13,19,22]. However, in a Korean study in 348 patients with coronary angioplasty it was found that atherothrombotic events occurred more frequently within 6 months after stent implantation among patients with the non-expressor genotype ( CYP3A5*3*3 ) than among those with the expressor genotype ( CYP3A5 * 1*1 or *1*3 ) [35].…”

“…CYP2C9 polymorphisms leading to decreased enzyme activity have been evaluated in several studies in relation to clopidogrel active metabolite exposure, inhibition of platelet aggregation and response [13,14,22,25]. Brandt et al [13] reported decreased active metabolite exposure, lower inhibition of platelet aggregation and poor responder status in healthy volunteers with CYP2C9 decreased function alleles ( *2 , *3 , or *11 ) after the administration of 300 mg clopidogrel [13].…”