1. ¹Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden
2. ²Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
3. ³Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

Correspondence: A-K Hamberg, (anna-karin.hamberg@roche.com)

Received 1 October 2006; Accepted 24 November 2006; Published online 14 February 2007.

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.