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Predicting the relative importance of genetic, clinical and demographic factors on warfarin dose in children using pharmacometric modelling
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.ORCID iD: 0000-0002-6368-2622
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
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(English)Article in journal (Other academic) Submitted
Abstract [en]

It is difficult to predict anticoagulation response to warfarin in children mainly because of a wide inter-individual variability in warfarin dose requirement. The present study objective was to identify important predictors of dose in children and to optimize a previous NONMEM warfarin model for a priori and a posteriori dose and INR predictions in children. Data from 163 warfarin treated children with underlying heart disease (median age 6.3 years) were used. CYP2C9 and VKORC1 genotype caused up to 4-fold and 2-fold differences in warfarin dose requirement, respectively. Other important predictors of warfarin dose were bodyweight, age, baseline and target INR, and time since initiation of therapy with lower doses during the initiation. CYP4F2 genotype had only a marginal effect on dose. The present study findings will aid the development of a personalised approach to warfarin therapy in children, in the pursuit of improving both efficacy and safety of anticoagulation therapy.

Keyword [en]
Pharmacometric model, warfarin, dose individualisation, children
National Category
Pediatrics
Research subject
Cardiology; Pharmaceutical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-197597OAI: oai:DiVA.org:uu-197597DiVA: diva2:613633
Funder
Swedish Heart Lung Foundation
Available from: 2013-03-29 Created: 2013-03-29 Last updated: 2016-02-19
In thesis
1. Pharmacometric Models for Individualisation of Warfarin in Adults and Children
Open this publication in new window or tab >>Pharmacometric Models for Individualisation of Warfarin in Adults and Children
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Warfarin is one of the most widely used anticoagulants. Therapy is complicated by warfarin’s narrow therapeutic range and pronounced variability in individual dose requirements. Although warfarin therapy is uncommon in children, it is crucial for children with certain congenital or acquired heart diseases. Treatment in children is especially difficult due to the lack of i) a decision support tool for efficient and consistent dose adjustments, and ii) a flexible warfarin formulation for accurate and reproducible dosing.

The overall aim of this thesis was to develop a PKPD-based pharmacometric model for warfarin that describes the dose-response relationship over time, and to identify important predictors that influence individual dose requirements both in adults and children. Special emphasis was placed on investigating the contribution of genetic factors to the observed variability.

A clinically useful pharmacometric model for warfarin has been developed using NONMEM. The model has been successfully reformulated into a KPD-model that describes the relationship between warfarin dose and INR response, and that is applicable to both adults and children. From a clinical perspective, this is a very important change since it allows the use of information on dose and INR that is available routinely. The model incorporates both patient and clinical characteristics, such as age, weight, CYP2C9 and VKORC1 genotype, and baseline and target INR, for the prediction of an individualised starting dose. It also enables the use of information from previous doses and INR observations to further individualise the dose a posteriori using a Bayesian forecasting method.

The NONMEM model has been transferred to a user-friendly, platform independent tool to aid use in clinical practice. The tool can be used for a priori and a posteriori individualisation of warfarin therapy in both adults and children. The tool should ensure consistent dose adjustment practices, and provide more efficient individualisation of warfarin dosing in all patients, irrespective of age, body weight, CYP2C9 or VKORC1 genotype, baseline or target INR. The expected outcome is improved warfarin therapy compared with empirical dosing, with patients achieving a therapeutic and stable INR faster and avoiding high INRs that increase the risk of bleeding.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 897
Keyword
warfarin, pharmacokinetics, pharmacodynamics, pharmacometrics, pharmacogenetics, dose individualisation, children
National Category
Clinical Medicine
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-197599 (URN)978-91-554-8653-2 (ISBN)
Public defence
2013-05-25, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Heart Lung Foundation
Available from: 2013-05-02 Created: 2013-03-29 Last updated: 2013-08-30Bibliographically approved

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Hamberg, Anna-KarinWadelius, MiaFriberg, Lena EJonsson, E Niclas

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