Factors influencing pharmacokinetics of warfarin in African-Americans: implications for pharmacogenetic dosing algorithms

Aim: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans. Methods: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. Results:CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. Conclusion: African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted3 November 2014