title: The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.
abstract: BACKGROUND
  Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.
  
  
  OBJECTIVE
  To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.
  
  
  METHODS
  Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.
  
  
  RESULTS
  Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).
  
  
  CONCLUSIONS
  Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.
authors.affiliation: Department of Biostatstics, Brownlow Street, University of Liverpool, Liverpool L69 3GS, UK. slane@liverpool.ac.uk
authors.forename: Steven
authors.initials: S
authors.lastname: Lane
authors.forename: Sameh
authors.initials: S
authors.lastname: Al-Zubiedi
authors.forename: Ellen
authors.initials: E
authors.lastname: Hatch
authors.forename: Ivan
authors.initials: I
authors.lastname: Matthews
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Jorgensen
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
authors.forename: Kayode
authors.initials: K
authors.lastname: Ogungbenro
authors.forename: Farhad
authors.initials: F
authors.lastname: Kamali
authors.forename: Dyfrig
authors.initials: D
authors.lastname: Hughes
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001824:Body Constitution / Q000187:drug effects; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014584:User-Computer Interface; D014859:Warfarin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C008091:6-hydroxywarfarin