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Characterising variability in warfarin dose requirements in children using modelling and simulation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. (Clinical pharmacogenomics)ORCID iD: 0000-0002-6368-2622
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2013 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 78, no 1, 158-169 p.Article in journal (Refereed) Published
Abstract [en]

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 optimise a published adult pharmacometric warfarin model for use in children.

RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-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 warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

Place, publisher, year, edition, pages
2013. Vol. 78, no 1, 158-169 p.
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Clinical Laboratory Medicine
Identifiers
URN: urn:nbn:se:uu:diva-222626DOI: 10.1111/bcp.12308ISI: 000337975400016PubMedID: 24330000OAI: oai:DiVA.org:uu-222626DiVA: diva2:711957
Funder
Swedish Heart Lung FoundationSwedish Research Council, Medicine 523-2008-5568 521-2011-2440
Available from: 2014-04-11 Created: 2014-04-11 Last updated: 2017-12-05Bibliographically approved

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Hamberg, Anna-KarinWadelius, MiaFriberg, Lena E

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Clinical pharmacogenomics and osteoporosisDepartment of Pharmaceutical Biosciences
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