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

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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.

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Data Availability

The data underlying this study will be available based on reasonable request to the corresponding authors.

Code Availability

The analytic code will be available upon request pending application and approval.

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Author notes

  1. Xiaoye Li and Zhichun Gu contributed equally to this article.

Authors and Affiliations

  1. Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China

    Xiaoye Li, Zi Wang, Qing Xu & Qianzhou Lv

  2. Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Zhichun Gu

  3. Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China

    Chunlai Ma

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  1. Xiaoye Li
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  4. Qing Xu
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Contributions

Xiaoye Li, Zhichun Gu, Chunlai, and Qianzhou Lv contributed to the study conception and design. Zi Wang and Qing Xu contributed to the acquisition of data. Xiaoye Li and Zhichun Gu contributed to the analysis and interpretation of data. Xiaoye Li and Qianzhou Lv contributed to the drafting of the manuscript. Chunlai Ma and Qianzhou Lv contributed to critical revision. All of the authors agreed to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Chunlai Ma or Qianzhou Lv.

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Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. The Ethics Committee of Zhongshan Hospital, Fudan University, approved this study.

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Informed consent was obtained from all individual participants included in the study.

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The authors declare no competing interests.

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Li, X., Gu, Z., Wang, Z. et al. Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07495-4

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