A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants

Abstract

The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an "acenocoumarol-dose genotype score" (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (> 28 mg/week) compared with the low-dose (< 7 mg/week) group (mean(SEM) of 84.1+/-3.4 vs. 62.2+/-4.8, P = 0.008). An AGS > 70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112-10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation.

Figure 1. Acenoumarol-dose Genotype Score and drug dose.

Upper panel: Acenoumarol-dose Genotype Score (0–100) by dose categories. Values are means and standard error. Post-hoc comparisons indicated that the AGS was significantly lower (P = 0.008) in low-dose vs. high-dose group. Lower panel: Frequency distribution of Acecoumarol-dose Genotype Score in the low-, medium-, and high-dose groups.