Pharmacogenetic testing for personalization of warfarin dosing

Main Article Content

O. O. Melnyk

Abstract

The sensitivity to warfarin is influenced by genetic factors, which are determined by polymorphisms of the genes CYP2C9 and VKORC1. In case of the wild type – CYP2C9*1, the rate of warfarin metabolism is standard. In the presence of variants of CYP2C9*2 and CYP2C9*3, the activity of the enzyme is reduced, therefore these alleles are «slow metabolizers» and patients need a lower, in comparison with the standard, dose of warfarin. VKORC1 (Vitamin K Epoxide Reductase Complex, subunit 1) is a main enzyme that activates vitamin K. The polymorphisms of VKORC1 can significantly alter pharmacodynamics of warfarin and the requirements for a maintenance dose. Patients with 1639A (rs992323) and 1173T (rs9934438) alleles require lower dose of warfarin (mean dose 24–26 mg/week) compared to 35 mg/week for wild type. While patients with 9041A (rs7294) require a higher dose of warfarin (an average dose 40 mg/week). With timely performance of pharmacogenetic testing it may be possible to identify patients who need an individual dose of warfarin and accordingly to reduce the percentage of complications.

Article Details

Keywords:

warfarin, pharmacogenetic testing, CYP2C9, VKORC1

References

Кропачева Е.С., Панченко Е.П. Сравнение эффективности и безопасности длительной терапии варфарином и аценокумаролом у больных с мерцательной аритмией // Клиниче­­­ская медицина.– 2005.– № 1.– С. 24–27.

Кукес В.Г. Клиническая фармакология: учебник для ву­­­­зов.– М.: Гэотар, 2009.– 1056 с.

Сычев Д.А., Кропачева Е.С., Игнатьев И.В. и др. Фар­­­макогенетика непрямых антикоагулянтов: значение генотипа в повышении эффективности и безопасности терапии // Кардиология.– 2006.– № 7.– С. 72–78.

Сычев Д.А. Антикоагулянтное действие и безопасность применения варфарина при его дозировании, основанном на результатах фармакогенетического тестирования: результаты первого российского проспективного пилотного исследования // Кардиология.– 2010.– № 5.– С. 42–46.

Copland M., Walker I.D., Tait R.C. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation // Arch. Intern. Med.– 2001.– Vol. 161 (17).– P. 2125–2128.

D’Andrea G., D’Ambrosio R.L., Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin // Blood.– 2005.– Vol. 105.– P. 645–649.

Food and Drugs Administration, Table of Pharmacogenomic Biomarkers in Drug Labeling. http:// www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/cm083378.htm.

Gage B.F., Eby C., Johnson J.A. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin // Clin. Pharmacol. Ther.– 2008.– Vol. 84.– P. 326–331.

Gage B.F., Eby C., Milligan P.E. et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin // Thromb Haemost.– 2004.– Vol. 91.– P. 87–94.

Geisen C., Watzka M., Sittinger K. et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation // Thromb Haemost.– 2005.– Vol. 94.– P. 773–779.

Gorter J.W. Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups // Neurology.– 1999.– Vol. 53, N 6.– P. 1319–1327.

Heimark L.D., Wienkers L., Kunze K. et al. The mechanism of the interaction between amiodarone and warfarin in humans // Clin. Pharmacol Ther.– 1992.– Vol. 51.– P. 398–407.

Herman D., Peternel P., Stegnar M. et al. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement // Thromb. Haemost.– 2006.– Vol. 95.– P. 782–787.

Klein T.E., Altman R.B., Eriksson N. et al. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data // New Engl. J. Med.– 2009.– Vol. 360, N 8.– P. 753–764.

Mazur-Bialy A.I., Zdebska K., Wypasek E., Undas A. Repeated bleeding complications during therapy with vitamin K antagonists in a patient with the VKORC1*2A and the CYP2C9*3/*3 alleles: genetic testing to support switching to new oral anticoagulants // Thromb. Res.– 2013.– Vol. 131, N 3.– P. 279–280.

Rettie A.E., Farin F.M., Beri N.G. et al. A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9 // Br. J. Clin. Pharmacol.– 2006.– Vol. 62.– P. 617–620.

Rieder M.J., Reiner A.P., Gage B.F. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose // New Engl. J. Med.– 2005.– Vol. 352.– P. 2285–2293.

Wadelius M., Chen L.Y., Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose // Pharmacogenomics J.– 2005.– Vol. 5.– P. 262–270.

Yuan H.Y., Chen J.J., Lee M.T. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity// Hum. Mol. Genet.– 2005.– Vol. 14.– P. 1745–1751.

Most read articles by the same author(s)

1 2 3 4 5 6 7 8 9 10 > >>