Abstract
The clinical utility of pharmacogenetic information during warfarin induction therapy was assessed in Asians. A prospective randomized trial in Chinese patients was performed to compare responses of warfarin between genotype-guided vs. standard dosing groups. Population pharmacokinetic-pharmacodynamic(PK-PD)analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), the normal prothrombin concentration (NPT)as a coagulation marker and anticoagulation response(INR). We estimated the clearance of S-warfarin, CL(S), IC50 in the relationship between Cp(S)and NPT and the non-linear indexλin the relationship between NPT and INR. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analyses revealed that CYP2C9 ＊3 mutation and body surface area were covariates of CL(S), that VKORC1 and CYP4F2 polymorphisms were covariates of IC50, and that baseline NPT was a covariate of λ. To clarify PK-PD factors associated with the overanticoagulation response, obtained PK-PD parameters were compared between the patient groups with and without INRB4. CL(S)andλwere significantly lower in patients with INRB4 than in those with INR＜4 (P＜0.01). These results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the overanticoagulation response during warfarin initiation in Asians.
