Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations

Background: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. Methods: Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC₅₀) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. Results: Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC₅₀ showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 μg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 −1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC₅₀ contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. Conclusions: Although there were contrasting racial differences in CL(S) and EC₅₀ that impacted on the INR, the racial difference in EC₅₀ was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.