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A Pharmacometric Model Describing the Relationship Between Warfarin Dose and INR Response With Respect to Variations in CYP2C9, VKORC1, and Age
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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 Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2010 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 87, no 6, 727-734 p.Article in journal (Refereed) Published
Abstract [en]

The objective of the study was to update a previous NONMEM model to describe the relationship between warfarin dose and international normalized ratio (INR) response, to decrease the dependence of the model on pharmacokinetic (PK) data, and to improve the characterization of rare genotype combinations. The effects of age and CYP2C9 genotype on S-warfarin clearance were estimated from high-quality PK data. Thereafter, a temporal dose-response (K-PD) model was developed from information on dose, INR, age, and CYP2C9 and VKORC1 genotype, with drug clearance as a covariate. Two transit compartment chains accounted for the delay between exposure and response. CYP2C9 genotype was identified as the single most important predictor of required dose, causing a difference of up to 4.2-fold in the maintenance dose. VKORC1 accounted for a difference of up to 2.1-fold in dose, and age reduced the dose requirement by ~6% per decade. This reformulated K-PD model decreases dependence on PK data and enables robust assessment of INR response and dose predictions, even in individuals with rare genotype combinations.

Place, publisher, year, edition, pages
2010. Vol. 87, no 6, 727-734 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-124511DOI: 10.1038/clpt.2010.37ISI: 000278264000028PubMedID: 20410877OAI: oai:DiVA.org:uu-124511DiVA: diva2:317620
Available from: 2010-05-04 Created: 2010-05-04 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.
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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