title: Integration of genetic, clinical, and INR data to refine warfarin dosing.
abstract: Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
authors.affiliation: Department of Internal Medicine, Washington University, St Louis, Missouri, USA.
authors.forename: P
authors.initials: P
authors.lastname: Lenzini
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
authors.forename: S
authors.initials: S
authors.lastname: Kimmel
authors.forename: J L
authors.initials: JL
authors.lastname: Anderson
authors.forename: A L
authors.initials: AL
authors.lastname: Jorgensen
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: M D
authors.initials: MD
authors.lastname: Caldwell
authors.forename: N
authors.initials: N
authors.lastname: Limdi
authors.forename: J K
authors.initials: JK
authors.lastname: Burmester
authors.forename: M B
authors.initials: MB
authors.lastname: Dowd
authors.forename: P
authors.initials: P
authors.lastname: Angchaisuksiri
authors.forename: A R
authors.initials: AR
authors.lastname: Bass
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Eriksson
authors.forename: A
authors.initials: A
authors.lastname: Rane
authors.forename: J D
authors.initials: JD
authors.lastname: Lindh
authors.forename: J F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: B D
authors.initials: BD
authors.lastname: Horne
authors.forename: G
authors.initials: G
authors.lastname: Grice
authors.forename: P E
authors.initials: PE
authors.lastname: Milligan
authors.forename: C
authors.initials: C
authors.lastname: Eby
authors.forename: J
authors.initials: J
authors.lastname: Shin
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: D
authors.initials: D
authors.lastname: Kurnik
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
authors.forename: G
authors.initials: G
authors.lastname: McMillin
authors.forename: R C
authors.initials: RC
authors.lastname: Pendleton
authors.forename: R L
authors.initials: RL
authors.lastname: Berg
authors.forename: P
authors.initials: P
authors.lastname: Deloukas
authors.forename: B F
authors.initials: BF
authors.lastname: Gage
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods / Q000592:standards*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods; D018511:Systems Integration; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases