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Characterizing variability in warfarin dose requirements in children using modelling and simulation

Lookup NU author(s): Dr Tina Biss, Professor Farhad Kamali

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Abstract

Aims Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation. Methods Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimize a published adult pharmacometric warfarin model for use in children. Results Genotype effects in children were found to be comparable with what has been reported for adults, with CYP2C9 explaining up to a four-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a two-fold difference in dose (VKORC1G/Gvs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a three-fold difference in dose for a four-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children. Conclusions The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting on warfarin dose variability in children. With this new knowledge more individualized dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

Publication metadata

Author(s): Hamberg AK, Wadelius M, Friberg LE, Biss TT, Kamali F, Jonsson EN

Publication type: Article

Publication status: Published

Journal: British Journal of Clinical Pharmacology

Year: 2014

Volume: 78

Issue: 1

Pages: 158-169

Print publication date: 01/07/2014

Online publication date: 20/06/2014

Acceptance date: 25/11/2013

Date deposited: 16/10/2014

ISSN (print): 0306-5251

ISSN (electronic): 1365-2125

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/bcp.12308

DOI: 10.1111/bcp.12308

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