title: A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy.
abstract: The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.
authors.affiliation: Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden. anna-karin.hamberg@roche.com
authors.forename: A-K
authors.initials: AK
authors.lastname: Hamberg
authors.forename: M-L
authors.initials: ML
authors.lastname: Dahl
authors.forename: M
authors.initials: M
authors.lastname: Barban
authors.forename: M G
authors.initials: MG
authors.lastname: Scordo
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
authors.forename: V
authors.initials: V
authors.lastname: Pengo
authors.forename: R
authors.initials: R
authors.lastname: Padrini
authors.forename: E N
authors.initials: EN
authors.lastname: Jonsson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D015233:Models, Statistical; D010599:Pharmacokinetics; D011153:Population; D013237:Stereoisomerism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D004247:DNA; 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