Integration of genetic, clinical, and INR data to refine warfarin dosing

Abstract

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Figure 1. Pharmacogenetic predicted versus actual therapeutic doses in the internal and external validation cohorts (using an INR on day 4 of therapy)

Open circles represent individuals for whom no variants in CYP2C9 and VKORC1 were detected. Grey circles represent individuals who are carrying one variant allele (either VKORC1-1639 A or a *2 or *3 allele. Black circles represent individuals with at least two variants. The ‘P’ was an individual taking phenytoin. The ‘R’ was an individual taking rifampin.