A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical SciencesFaculty of Pharmacy, Department of Pharmaceutical Biosciences2007 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 81, no 4, 529-538 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 81, no 4, 529-538 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-12888DOI: 10.1038/sj.clpt.6100084ISI: 000245435900011PubMedID: 17301738OAI: oai:DiVA.org:uu-12888DiVA: diva2:40658