Clopidogrel and CYP2C19: pharmacogenetic testing ready for clinical prime time?

Dual antiplatelet therapy with clopidogrel and aspirin has become the mainstay of therapy for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCI). Many pharmacokinetic and pharmacodynamic studies have demonstrated substantial interindividual variation in antiplatelet response with clopidogrel, a significant proportion of which is explained by the variation in plasma concentrations of the clopidogrel active metabolite. Clopidogrel is a prodrug that requires bioactivation by the highly polymorphic enzyme CYP2C19 to form the active metabolite. The growing body of literature has implicated the loss-of-function cytochrome P450, family 2, subfamily C, polypeptide 19 variant (CYP2C19*2) variant with an increased risk of major cardiovascular events. This evidence prompted the US Food and Drug Administration (FDA) to implement a boxed warning on the clopidogrel label describing the relationship between CYP2C19 pharmacogenetics and drug response, emphasizing the diminished effectiveness in CYP2C19 poor metabolizers.