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

Rui Nagai, Minami Ohara, Larisa H. Cavallari, Katarzyna Drozda, Shitalben R. Patel, Edith A. Nutescu, Minoli A. Perera, Wenndy Hernandez, Naoko Kaneko, Manabu Hibiya, Harumi Takahashi*

*Corresponding author for this work

Research output: Contribution to journalReview article

13 Scopus citations

Abstract

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 m2/-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 languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalPharmacogenomics
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • African-American
  • CYP2C9 8
  • genotype
  • pharmacokinetics
  • warfarin

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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