Paediatric clinical pharmacology
Characterizing variability in warfarin dose requirements in children using modelling and simulation
Article first published online: 20 JUN 2014
© 2013 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
British Journal of Clinical Pharmacology
Volume 78, Issue 1, pages 158–169, July 2014
How to Cite
Hamberg, A.-K., Wadelius, M., Friberg, L. E., Biss, T. T., Kamali, F. and Jonsson, E. N. (2014), Characterizing variability in warfarin dose requirements in children using modelling and simulation. British Journal of Clinical Pharmacology, 78: 158–169. doi: 10.1111/bcp.12308
- Issue published online: 20 JUN 2014
- Article first published online: 20 JUN 2014
- Accepted manuscript online: 12 DEC 2013 11:00PM EST
- Manuscript Accepted: 25 NOV 2013
- Manuscript Received: 28 AUG 2013
- dose variability;
- PKPD modelling;
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.
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.
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 (VKORC1 G/G vs. 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.
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.