The impact of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms on apixaban trough concentration and bleeding risk in patients with atrial fibrillation.

Q2 Pharmacology, Toxicology and Pharmaceutics

Drug metabolism and personalized therapy Pub Date : 2024-07-01 eCollection Date: 2024-06-01 DOI:10.1515/dmpt-2024-0013

Alena I Skripka, Pavel M Krupenin, Olga N Kozhanova, Anna A Kudryavtseva, Ludmila V Fedina, Kristina A Akmalova, Pavel O Bochkov, Anastasiya A Sokolova, Dmitriy A Napalkov, Dmitriy A Sychev

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引用次数: 0

Abstract

Objectives: Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding.

Methods: A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.

Results: The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 μmol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding.

Conclusions: We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.

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ABCB1、CYP3A4 和 CYP3A5 基因多态性对心房颤动患者阿哌沙班谷浓度和出血风险的影响。

目的：阿哌沙班是一种直接口服抗凝剂，在全世界越来越多地被用于治疗和预防非瓣膜性心房颤动（房颤）患者的静脉血栓栓塞和缺血性中风。显然，提高药物治疗的有效性和安全性的方法之一是个性化治疗，其中包括药物遗传学和药代动力学检测。本研究旨在探讨 CYP3A4*22、CYP3A5*3 和 ABCB1 多态性对阿哌沙班药代动力学和出血风险的影响：这项前瞻性观察研究共纳入了84名患者。所有患者均接受阿哌沙班治疗，剂量为 5 或 2.5 毫克，每天两次。采用实时聚合酶链反应评估 ABCB1 基因（rs1045642 和 rs4148738）、CYP3A4*22（rs35599367）C>T、CYP3A5*3（rs776746）A>G 的单核苷酸多态性，并以血浆谷浓度/剂量（C/D）比值作为药代动力学指标：年龄大于 80 岁的患者 C/D 比值更高（F(1)=11.209，p=0.00124），且受血清肌酐（大于 133 μmol/L，F(1)=6.7，p=0.01124）的影响。ABCB1（rs1045642 和 rs4148738）、CYP3A5（rs776746）和 CYP3A4（rs35599367）多态性与阿哌沙班的 C/D 比值没有相关性。多变量逻辑回归分析表明，临床或遗传因素都不能预测出血的事实：我们报告的 ABCB1 基因多态性（rs1045642 和 rs4148738）、CYP3A4*22 (rs35599367) C>T、CYP3A5*3 (rs776746) A>G 与阿哌沙班治疗中的出血事件无明显关联。利用房颤患者的药物基因学和药代动力学信息对现有标准进行补充，将有助于进一步实现阿哌沙班治疗的个体化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug metabolism and personalized therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

2.30

自引率

0.00%

发文量

期刊介绍： Drug Metabolism and Personalized Therapy (DMPT) is a peer-reviewed journal, and is abstracted/indexed in relevant major Abstracting Services. It provides up-to-date research articles, reviews and opinion papers in the wide field of drug metabolism research, covering established, new and potential drugs, environmentally toxic chemicals, the mechanisms by which drugs may interact with each other and with biological systems, and the pharmacological and toxicological consequences of these interactions and drug metabolism and excretion. Topics: drug metabolizing enzymes, pharmacogenetics and pharmacogenomics, biochemical pharmacology, molecular pathology, clinical pharmacology, pharmacokinetics and drug-drug interactions, immunopharmacology, neuropsychopharmacology.