title: A pharmacometric model describing the relationship between warfarin dose and INR response with respect to variations in CYP2C9, VKORC1, and age.
abstract: The objective of the study was to update a previous NONMEM model to describe the relationship between warfarin dose and international normalized ratio (INR) response, to decrease the dependence of the model on pharmacokinetic (PK) data, and to improve the characterization of rare genotype combinations. The effects of age and CYP2C9 genotype on S-warfarin clearance were estimated from high-quality PK data. Thereafter, a temporal dose-response (K-PD) model was developed from information on dose, INR, age, and CYP2C9 and VKORC1 genotype, with drug clearance as a covariate. Two transit compartment chains accounted for the delay between exposure and response. CYP2C9 genotype was identified as the single most important predictor of required dose, causing a difference of up to 4.2-fold in the maintenance dose. VKORC1 accounted for a difference of up to 2.1-fold in dose, and age reduced the dose requirement by ~6% per decade. This reformulated K-PD model decreases dependence on PK data and enables robust assessment of INR response and dose predictions, even in individuals with rare genotype combinations.
authors.affiliation: Department of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden. anna-karin.hamberg@medsci.uu.se
authors.forename: A-K
authors.initials: AK
authors.lastname: Hamberg
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
authors.forename: J D
authors.initials: JD
authors.lastname: Lindh
authors.forename: M L
authors.initials: ML
authors.lastname: Dahl
authors.forename: R
authors.initials: R
authors.lastname: Padrini
authors.forename: P
authors.initials: P
authors.lastname: Deloukas
authors.forename: A
authors.initials: A
authors.lastname: Rane
authors.forename: E N
authors.initials: EN
authors.lastname: Jonsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002986:Clinical Trials as Topic; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D013997:Time Factors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000925:Anticoagulants; 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