Dataset Information

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

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 (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.

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.

SUBMITTER: Hamberg AK

PROVIDER: S-EPMC4168390 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Hamberg Anna-Karin AK Wadelius Mia M Friberg Lena E LE Biss Tina T TT Kamali Farhad F Jonsson E Niclas EN

British journal of clinical pharmacology 20140701 1

<h4>Aims</h4>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.<h4>Methods</h4>Clinical, demographic and genetic data from 163 children with a median age o ...[more]

PMID: 24330000

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Dataset Information

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

Aims

Methods

Results

Conclusions

Publications

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

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