Li Xiaoye, Gu Zhichun, Wang Zi, Xu Qing, Ma Chunlai, Lv Qianzhou
Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Cardiovasc Drugs Ther. 2024 Dec;38(6):1315-1325. doi: 10.1007/s10557-023-07495-4. Epub 2023 Aug 5.
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.
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) of rivaroxaban, coagulation indicators at the C including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes.
Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban C, PT values than that of wild-type. Furthermore, a positive relationship was revealed between C and PT (r = 0.212, p = 0.007), while no significant correlation was found between C 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).
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.
本研究旨在基于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）对非瓣膜性心房颤动（NVAF）患者利伐沙班临床结局的影响。
开展一项前瞻性研究，纳入165例接受利伐沙班治疗的NVAF患者。对CYP3A4（rs2242480、rs2246709、rs3735451和rs4646440）和CYP3A5（rs776746）进行基因分型，以探讨其对利伐沙班谷浓度（C）、C时的凝血指标（包括活化部分凝血活酶时间（APTT）和凝血酶原时间（PT））以及临床结局的影响。
具有突变基因型CYP3A4（rs2242480、rs2246709和rs3735451）和CYP3A5（rs776746）的患者的利伐沙班C水平和PT值高于野生型。此外，C与PT之间呈正相关（r = 0.212，p = 0.007），而C与APTT之间未发现显著相关性。关于临床结局，rs3735451上的次要等位基因携带者和rs2246709上的次要等位基因（A）携带者与轻微出血发生率较高相关（分别为p = 0.028和p = 0.038），并被确定为接受利伐沙班治疗的轻微出血的独立危险因素（分别为p = 0.024和p = 0.036），经受试者工作特征（ROC）曲线验证（AUC = 0.8956，95% CI：0.829 - 0.962）。
CYP3A4多态性（rs2242480、rs2246709和rs3735451）和CYP3A5 rs776746与利伐沙班PK/PD的变化有关。rs3735451上的次要等位基因（C）携带者和rs2246709上的次要等位基因（A）携带者与临床结局相关。
