title: Factors influencing pharmacokinetics of warfarin in African-Americans: implications for pharmacogenetic dosing algorithms.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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 submitted 3 November 2014.
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo 204 8588, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Nagai
authors.forename: Minami
authors.initials: M
authors.lastname: Ohara
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Drozda
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Edith A
authors.initials: EA
authors.lastname: Nutescu
authors.forename: Minoli A
authors.initials: MA
authors.lastname: Perera
authors.forename: Wenndy
authors.initials: W
authors.lastname: Hernandez
authors.forename: Naoko
authors.initials: N
authors.lastname: Kaneko
authors.forename: Manabu
authors.initials: M
authors.lastname: Hibiya
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001830:Body Surface Area; D001835:Body Weight; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: African–American; CYP2C9*8; genotype; pharmacokinetics; warfarin