Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation.

IF 3.1 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Drugs and Therapy Pub Date : 2024-12-01 Epub Date: 2023-08-05 DOI:10.1007/s10557-023-07495-4

Xiaoye Li, Zhichun Gu, Zi Wang, Qing Xu, Chunlai Ma, Qianzhou Lv

{"title":"Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation.","authors":"Xiaoye Li, Zhichun Gu, Zi Wang, Qing Xu, Chunlai Ma, Qianzhou Lv","doi":"10.1007/s10557-023-07495-4","DOIUrl":null,"url":null,"abstract":"Purpose: This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects.Method: A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (Ctrough) of rivaroxaban, coagulation indicators at the Ctrough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes.Results: Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban Ctrough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between Ctrough and PT (r = 0.212, p = 0.007), while no significant correlation was found between Ctrough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962).Conclusion: The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":"1315-1325"},"PeriodicalIF":3.1000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Drugs and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10557-023-07495-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/8/5 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects.

Method: A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (C_trough) of rivaroxaban, coagulation indicators at the C_trough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes.

Results: Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban C_trough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between C_trough and PT (r = 0.212, p = 0.007), while no significant correlation was found between C_trough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962).

Conclusion: The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

突变CYP3A4/5通过影响心房颤动患者利伐沙班药代动力学和药效学与临床结局相关

目的：本研究旨在从药代动力学和药效学（PK/PD）方面探讨单核苷酸多态性编码的细胞色素P450酶（CYP3A4/5）对利伐沙班治疗非瓣瓣膜性房颤（NVAF）患者临床结局的影响。方法：对165例接受利伐沙班治疗的非瓣膜性房颤患者进行前瞻性研究。对CYP3A4 （rs2242480、rs2246709、rs3735451和rs4646440）和CYP3A5 （rs776746）进行基因分型，探讨它们对利伐沙班谷血药浓度（Ctrough）、谷血药浓度凝血指标(包括活化的部分凝血活酶时间（APTT）和凝血酶原时间（PT）以及临床结果的影响。结果：突变型CYP3A4 （rs2242480、rs2246709和rs3735451）和CYP3A5 （rs776746）患者的利伐沙班cough、PT值高于野生型患者。此外，Ctrough与PT呈正相关（r = 0.212, p = 0.007），而Ctrough与APTT无显著相关。在临床结果方面，rs3735451和rs2246709的小等位基因(A)携带者与小出血发生率较高相关（p = 0.028和p = 0.038），被确定为利伐沙班治疗小出血的独立危险因素（p = 0.024和p = 0.036），并验证了受试者工作特征（ROC）曲线（AUC = 0.8956, 95% CI: 0.829-0.962）。结论：CYP3A4基因多态性（rs2242480、rs2246709和rs3735451）和CYP3A5基因多态性（rs776746）与利伐沙班PK/PD变异相关。rs3735451小等位基因(C)携带者和rs2246709小等位基因(A)携带者与临床结果相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cardiovascular Drugs and Therapy 医学-心血管系统

CiteScore

8.30

自引率

0.00%

发文量

110

审稿时长

4.5 months

期刊介绍： Designed to objectively cover the process of bench to bedside development of cardiovascular drug, device and cell therapy, and to bring you the information you need most in a timely and useful format, Cardiovascular Drugs and Therapy takes a fresh and energetic look at advances in this dynamic field. Homing in on the most exciting work being done on new therapeutic agents, Cardiovascular Drugs and Therapy focusses on developments in atherosclerosis, hyperlipidemia, diabetes, ischemic syndromes and arrhythmias. The Journal is an authoritative source of current and relevant information that is indispensable for basic and clinical investigators aiming for novel, breakthrough research as well as for cardiologists seeking to best serve their patients. Providing you with a single, concise reference tool acknowledged to be among the finest in the world, Cardiovascular Drugs and Therapy is listed in Web of Science and PubMed/Medline among other abstracting and indexing services. The regular articles and frequent special topical issues equip you with an up-to-date source defined by the need for accurate information on an ever-evolving field. Cardiovascular Drugs and Therapy is a careful and accurate guide through the maze of new products and therapies which furnishes you with the details on cardiovascular pharmacology that you will refer to time and time again.