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Prediction of warfarin dose: why, when and how?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. (Clinical pharmacogenomics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.ORCID iD: 0000-0002-6368-2622
2012 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, 429-440 p.Article, review/survey (Refereed) Published
Abstract [en]

Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

Place, publisher, year, edition, pages
2012. Vol. 13, no 4, 429-440 p.
Keyword [en]
dosing algorithm, human CYP2C9 protein, human VKORC1 protein, pharmacogenetics models, statistical regression analysis, warfarin
National Category
Medical and Health Sciences
Research subject
Clinical Pharmacology
URN: urn:nbn:se:uu:diva-170013DOI: 10.2217/pgs.11.184ISI: 000301098000018PubMedID: 22379999OAI: oai:DiVA.org:uu-170013DiVA: diva2:508173
Swedish Research Council, K2012-66X-22105-01-3
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2016-09-30Bibliographically approved
In thesis
1. On the Prediction of Warfarin Dose
Open this publication in new window or tab >>On the Prediction of Warfarin Dose
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 79 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 773
Warfarin, pharmacogenetics, prediction models, Dosing algorithm, GWAS, VKORC1, CYP2C9
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
urn:nbn:se:uu:diva-172864 (URN)978-91-554-8359-3 (ISBN)
Public defence
2012-06-05, Enghoffsalen, Akademiska sjukhuset, ingång 50, bv, Uppsala, 09:00 (Swedish)
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

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