Determinants of the Over-Anticoagulation Response during Warfarin Initiation Therapy in Asian Patients Based on Population Pharmacokinetic-Pharmacodynamic Analyses

To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC 50 . We also analyzed the nonlinear relationship between NPT inhibition and the increase in INR to derive the non-linear index l. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC 50 , and that baseline NPT was a predictor of l. CL(S) and l were significantly lower in patients with INR$4 than in those with INR,4 (190 mL/h vs 265 mL/h, P,0.01 and 3.2 vs 3.7, P,0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR$4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.