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A pharmacometric model describing the relationship between warfarin dose and INR response with respect to variations in CYP2C9, VKORC1, and age.

Authors
  • Hamberg, A-K
  • Wadelius, M
  • Lindh, J D
  • Dahl, M L
  • Padrini, R
  • Deloukas, P
  • Rane, A
  • Jonsson, E N
Type
Published Article
Journal
Clinical Pharmacology & Therapeutics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jun 01, 2010
Volume
87
Issue
6
Pages
727–734
Identifiers
DOI: 10.1038/clpt.2010.37
PMID: 20410877
Source
Medline
License
Unknown

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.

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