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A Pharmacokinetic Drug–Drug Interactions Study between Entecavir and Hydronidone, a Potential Novel Antifibrotic Small Molecule, in Healthy Male Volunteers

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Abstract

Introduction

Hepatic fibrosis is an inevitable process of hepatic sclerosis, malignancy, and insufficiency, and hydronidone is an innovative antifibrosis drug. This study focus on the pharmacokinetic interaction of hydronidone and entecavir in healthy Chinese male subjects.

Methods

An open-label, three-period, multiple-dosage, self-controlled clinical trial was executed in 12 healthy male subjects. In period 1, the subjects took hydronidone 60 mg, q8h, for 7 days. In period 2, they were given entecavir 0.5 mg once daily for 9 days. Then, hydronidone and entecavir were given in combination for 6 days (days 20–26). Blood samples were taken up to 24 h post-dosing, while pre-dose blood samples were drawn on days 7, 19, and 26.

Results

The area under the curve (AUC)0–t_ss of entecavir slightly increased from 15.56 ± 2.67 to 16.17 ± 2.77 ng h/ml with coadministration with hydronidone, while the other pharmacokinetic parameters of hydronidone and entecavir were comparable between monotherapy and combination therapy. The geometric mean ratios (GMRs) [90% confidence intervals (CIs)] of Cmax_ss, AUC0–t_ss, and AUC0–∞_ss of entecavir after coadministration compared with entecavir alone were 107.21% (97.04–118.45%), 103.85% (100.94–106.83%), and 110.81% (97.19–126.33%), respectively. And the GMRs and 90% CIs of Cmax,ss, AUC0–t_ss, and AUC0–∞_ss for combination therapy compared with the hydronidone monotherapy group were 102.72% (84.21–125.29%), 106.52% (97.06–116.90%), and 108.86% (96.42–122.89%), respectively.

Conclusions

There was no drug–drug interaction between hydronidone and entecavir in healthy male volunteers. However, multiple doses of hydronidone have a risk with increasing exposure to entecavir in vivo, which needs to be further clarified.

Registration number

ChiCTR2200059683 (retrospectively registered).

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Acknowledgements

We thank the participants of the study.

Funding

This work was supported by National Natural Science Foundation of China (82104274, 82173902, 81874326), General Project of Wuhan Health Research Fund (WX21D55), Project of Beijing Medical Award Foundation (YXJL-2018-0095-0068). The Rapid Service Fee was funded by these foundations.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Study concept and design (Shaojun-Shi, Yani-Liu), data acquisition and interpretation (all authors), literature research, statistical analysis and drafting of the manuscript (Rui-Zhang), approval of the final version (all author), administrative, technical, or material support (Shaojun-Shi), and study supervision (Yani-Liu). All authors have made a significant contribution to this study.

Disclosures

Shaojun-Shi, Yani-Liu, Rui-zhang, Peixia-Li, Pengpeng-Guo; Jinping-Zhou; Jing-Wan; Chunxiao-Yang and Jiali-Zhou declare that they have no competing interests.

Compliance with Ethics Guidelines

The trials were performed conform to Good Clinical Practice (GCP) standards of China National Medical Products Administration (NMPA)[20], the International Conference on Harmonisation GCP guidelines and the Declaration of Helsinki (as revised in Brazil, 2013). The approval number of this study was 2011S00434 which granted by NMPA, and the independent ethics committee of Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China) agreed to implement this protocol [approval no. (2014)185]. All volunteers voluntarily signed informed consent.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Author notes

  1. Yani Liu & Shaojun Shi

    Present address: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

  2. Yani Liu and Shaojun Shi made equal contributions to this work.

Authors and Affiliations

  1. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Rui Zhang, Peixia Li, Pengpeng Guo, Jinping Zhou, Jing Wan, Chunxiao Yang & Jiali Zhou

  2. Union Jiangnan Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China

    Shaojun Shi

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Correspondence to Yani Liu or Shaojun Shi.

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Zhang, R., Li, P., Guo, P. et al. A Pharmacokinetic Drug–Drug Interactions Study between Entecavir and Hydronidone, a Potential Novel Antifibrotic Small Molecule, in Healthy Male Volunteers. Adv Ther 40, 658–670 (2023). https://doi.org/10.1007/s12325-022-02377-x

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