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A Bayesian decision support tool for efficient dose individualization of warfarin in adults and children
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2015 (English)In: BMC Medical Informatics and Decision Making, ISSN 1472-6947, Vol. 15, no 7Article in journal (Refereed) Published
Abstract [en]

Warfarin is the most widely prescribed anticoagulant for prevention and treatment of thromboembolic events. Although highly effective, the use of warfarin is limited by a narrow therapeutic range combined with a more than ten-fold difference in the dose required for adequate anticoagulation in adults. For each patient, an optimal dose that leads to a favourable balance between the wanted antithrombotic effect and the risk of bleeding, measured as the prothrombin time International Normalised Ratio (INR), must be found. A model capable of describing the time-course of the INR response to warfarin therapy can be used to aid dose selection, both before starting therapy (a priori dose prediction) and after therapy has been initiated (a posteriori dose revision). In this paper we describe the transfer of a population PKPD-model for warfarin developed in NONMEM to a platform independent decision support tool written in Java. The tool proved capable of solving a system of differential equations representing the pharmacokinetics and pharmacodynamics of warfarin, with a performance comparable to NONMEM. To estimate an a priori dose the user provides information on body weight, age, CYP2C9 and VKORC1 genotype, baseline and target INR. With addition of information about previous doses and INR observations, the tool will use a Bayesian forecasting method to suggest an a posteriori dose, i.e. the dose with the highest probability to result in the desired INR. Results are displayed as the predicted dose per day and per week, and graphically as the predicted INR curve. The tool can also be used to predict INR following any given dose regimen, e.g. a loading-dose regimen. We believe it will provide a clinically useful tool for initiating and maintaining warfarin therapy in the clinic. It will ensure consistent dose adjustment practices between prescribers, and provide more efficient individualization of warfarin dosing in both children and adults.

Place, publisher, year, edition, pages
2015. Vol. 15, no 7
Keyword [en]
PK/PD-model, Population model, warfarin, dosing, Bayesian
National Category
Other Clinical Medicine Engineering and Technology
Research subject
Pharmacokinetics and Drug Therapy; Clinical Pharmacology; Engineering Science with specialization in Nanotechnology and Functional Materials
URN: urn:nbn:se:uu:diva-197598DOI: 10.1186/s12911-014-0128-0ISI: 000349352900001OAI: diva2:613634
Swedish Heart Lung Foundation
Available from: 2013-03-29 Created: 2013-03-29 Last updated: 2016-02-22Bibliographically approved
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 897
warfarin, pharmacokinetics, pharmacodynamics, pharmacometrics, pharmacogenetics, dose individualisation, children
National Category
Clinical Medicine
Research subject
Clinical Pharmacology
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)
Swedish Heart Lung Foundation
Available from: 2013-05-02 Created: 2013-03-29 Last updated: 2013-08-30Bibliographically approved

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Clinical pharmacogenomics and osteoporosisNanotechnology and Functional MaterialsDepartment of Pharmaceutical Biosciences
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