泰诺福韦的新型肝靶向前药 Hepenofovir 在中国健康受试者中单

StephenW

泰诺福韦的新型肝靶向前药 Hepenofovir 在中国健康受试者中单次和多次递增剂量的药代动力学、安全性和耐受性的首次人体研究
张红 1 , 高磊 1 , 金峰楼 1 , 吴敏 1 , 陈红 1 , 杨立志 2 , 刘景瑞 1 , 朱小雪 1 , 李小娇 1 , 李翠云 1 , 王梦 1 , 刘成娇 1 , 郭伟博3、王远 3、高忠强 3、韩磊 3、王戴迪 3、金伟丽 3、丁艳华 1
隶属关系
隶属关系

    1
    【作者单位】： 吉林大学第一医院Ⅰ期临床研究中心;
    2
    吉林省长春市南关区妇幼保健与计划生育服务中心。
    3
    西安欣通医药研究有限公司，西安，中国。

    PMID：35662718 PMCID：PMC9161552 DOI：10.3389/fphar.2022.873588

抽象的

目的：替诺福韦的新型肝靶向前药Hepenofovir已被开发用于治疗慢性乙型肝炎（CHB）。这是一项评估单次和多次递增剂量 hepenofovir 在中国健康受试者中的药代动力学 (PK) 和耐受性的首次人体研究。方法：这项 Ia 期研究包括两部分：在禁食条件下进行的双盲、随机、安慰剂对照单剂量递增 (SAD) (25-200 mg) 研究，包括食物效应调查 (200 mg) 和在禁食条件下进行多次递增剂量 (MAD) (25 mg) 研究。结果：健康的中国受试者对 Hepenofovir 的耐受性良好。 hepenofovir 和安慰剂组之间的不良反应发生率没有显着差异。 Hepenofovir 在给药后被迅速吸收并代谢成替诺福韦。在健康参与者中，hepenofovir 和tenofovir 的中位 Tmax 分别为 0.33-0.50 h 和 0.62-0.75 h，其平均半衰期分别为 2.5-12.3 h 和 49.7-53.8 h。替诺福韦的全身暴露与剂量成比例增加。 hepenofovir 和tenofovir 的平均蓄积指数分别为 1.1 和 1.8。此外，食物可以降低 hepenofovir 和tenofovir 的 Cmax，但不影响它们的曲线下面积 (AUC)。结论： Hepenofovir 显示出良好的安全性和 PK 特征，支持进一步评估其在 CHB 患者中的安全性和有效性。临床试验注册号：试验在中国临床试验网（http://www.chinadrugtrials.org.cn/index.html#CTR20191953）注册。

关键词：乙肝；临床试验;药代动力学；前药；替诺福韦。

版权所有 © 2022 张、高、娄、吴、陈、杨、刘、朱、李、李、王、刘、郭、王、高、韩、王、金、丁。
利益冲突声明

WG、YW、ZG、LH、DW 和 WJ 受雇于西安欣通医药研究有限公司。其余作者声明，该研究是在没有任何可能被解释为潜在商业或财务关系的情况下进行的。利益冲突。

StephenW

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects
Hong Zhang  1 , Lei Gao  1 , Jinfeng Lou  1 , Min Wu  1 , Hong Chen  1 , Lizhi Yang  2 , Jingrui Liu  1 , Xiaoxue Zhu  1 , Xiaojiao Li  1 , Cuiyun Li  1 , Meng Wang  1 , Chengjiao Liu  1 , Weibo Guo  3 , Yuan Wang  3 , Zhongqiang Gao  3 , Lei Han  3 , Daidi Wang  3 , Weili Jin  3 , Yanhua Ding  1
Affiliations
Affiliations

    1
    Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China.
    2
    Nanguan District Maternal and Child Health and Family Planning Service Center of Changchun, Jilin, China.
    3
    Xi'an Xintong Pharmaceutical Research Co. Ltd., Xi'an, China.

    PMID: 35662718 PMCID: PMC9161552 DOI: 10.3389/fphar.2022.873588

Abstract

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects. Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25-200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions. Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33-0.50 h and 0.62-0.75 h, respectively, and their mean half-life was 2.5-12.3 h and 49.7-53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC). Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients. Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

Keywords: HBV; clinical trial; pharmacokinetics; prodrug; tenofovir.

Copyright © 2022 Zhang, Gao, Lou, Wu, Chen, Yang, Liu, Zhu, Li, Li, Wang, Liu, Guo, Wang, Gao, Han, Wang, Jin and Ding.
Conflict of interest statement

WG, YW, ZG, LH, DW, and WJ are employed by Xi’an Xintong Pharmaceutical Research Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

StephenW

https://www.frontiersin.org/arti ... har.2022.873588/pdf