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A PK–PD Model for Predicting the Impact of Age, CYP2C9 , and VKORC1 Genotype on Individualization of Warfarin Therapy
Author(s) -
Hamberg AK,
Dahl ML,
Barban M,
Scordo M G,
Wadelius M,
Pengo V,
Padrini R,
Jonsson E N
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100084
Subject(s) - warfarin , vkorc1 , cyp2c9 , pharmacodynamics , nonmem , medicine , clinical pharmacology , population , anticoagulant , pharmacokinetics , pharmacology , pharmacogenomics , genotype , biology , atrial fibrillation , genetics , gene , environmental health , cytochrome p450 , metabolism
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. Clinical Pharmacology & Therapeutics (2007) 81 , 529–538. doi: 10.1038/sj.clpt.6100084 ; published online 14 February 2007