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Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. W...

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Autores principales: Attelind, Sofia, Hallberg, Pär, Wadelius, Mia, Hamberg, Anna-Karin, Siegbahn, Agneta, Granger, Christopher B., Lopes, Renato D., Alexander, John H., Wallentin, Lars, Eriksson, Niclas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9515473/
https://www.ncbi.nlm.nih.gov/pubmed/36186466
http://dx.doi.org/10.3389/fgene.2022.982955
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author Attelind, Sofia
Hallberg, Pär
Wadelius, Mia
Hamberg, Anna-Karin
Siegbahn, Agneta
Granger, Christopher B.
Lopes, Renato D.
Alexander, John H.
Wallentin, Lars
Eriksson, Niclas
author_facet Attelind, Sofia
Hallberg, Pär
Wadelius, Mia
Hamberg, Anna-Karin
Siegbahn, Agneta
Granger, Christopher B.
Lopes, Renato D.
Alexander, John H.
Wallentin, Lars
Eriksson, Niclas
author_sort Attelind, Sofia
collection PubMed
description Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59–243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.
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spelling pubmed-95154732022-09-29 Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events Attelind, Sofia Hallberg, Pär Wadelius, Mia Hamberg, Anna-Karin Siegbahn, Agneta Granger, Christopher B. Lopes, Renato D. Alexander, John H. Wallentin, Lars Eriksson, Niclas Front Genet Genetics Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59–243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events. Frontiers Media S.A. 2022-09-14 /pmc/articles/PMC9515473/ /pubmed/36186466 http://dx.doi.org/10.3389/fgene.2022.982955 Text en Copyright © 2022 Attelind, Hallberg, Wadelius, Hamberg, Siegbahn, Granger, Lopes, Alexander, Wallentin and Eriksson. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Attelind, Sofia
Hallberg, Pär
Wadelius, Mia
Hamberg, Anna-Karin
Siegbahn, Agneta
Granger, Christopher B.
Lopes, Renato D.
Alexander, John H.
Wallentin, Lars
Eriksson, Niclas
Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title_full Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title_fullStr Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title_full_unstemmed Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title_short Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
title_sort genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9515473/
https://www.ncbi.nlm.nih.gov/pubmed/36186466
http://dx.doi.org/10.3389/fgene.2022.982955
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