Implementing genotype-guided antithrombotic therapy

Abstract

Genotyping has the potential to improve the efficacy and safety of major antithrombotic drugs. For warfarin, the stable maintenance dose varies from 1-10 mg/day. The VKORC1 -1639G>A allele and the CYP2C9*2 and *3 alleles (cumulative frequency: 90% in Asians, 65% in Europeans and 20% in Africans), explain 45% of response variability in European and 30% in African populations. The large clinical trials COAG and EU-PACT will define the extent to which pharmacogenetic dosing affects the safety and efficacy of warfarin and coumarin derivatives. The platelet inhibitor clopidogrel requires activation by the CYP2C19 enzyme. CYP2C19*2 and *3 alleles (cumulative frequency: 20-50%) produce null enzyme activity, and their presence attenuates platelet inhibition and increases cardiovascular events. The US FDA-mandated drug labeling recognizes the relevance of genotyping in the selection and dosing of both warfarin and clopidogrel.

Figures

Figure 1. The vitamin K cycle

The VKORC1 gene product reduces vitamin K and the cytochrome p450 2C9 protein metabolizes warfarin. The (red) X indicates inhibition by warfarin.

Figure 2. Predicted mean decreases in warfarin dose (mg/day) in 127 outpatients from a preventive cardiology clinic with reference sequences and single, double, triple or quadruple polymorphisms for CYP2C9 and VKORC1 genes

The decreases were calculated using published formulae [41,42] that employ age, gender, weight, height, CYP2C9 genotype and VKORC1 genotype. The purple areas indicate ranges of predicted dose reductions. The upper and lower borders represent the reductions according to the formulae of Zhu et al. [41] and Sconce et al. [42], respectively. Figure taken from [12].

Figure 3. Clopidogrel activation to R130964 by CYP2C19: essential step for therapeutic effect