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

Frontiers in Pharmacology

Lizhi Yang¹  Jingrui Liu²  Xiaojiao Li²  Lei Gao²  Xiaoxue Zhu²  Min Wu²  Yanhua Ding²  Jinfeng Lou²  Hong Chen²  Meng Wang²  Chengjiao Liu²  Hong Zhang²  Cuiyun Li²  Daidi Wang³  Weibo Guo³  Yuan Wang³  Lei Han³  Weili Jin³  Zhongqiang Gao³ 

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

关键词: clinical trial;    pharmacokinetics;    prodrug;    tenofovir;    HBV;   

DOI  :  10.3389/fphar.2022.873588

来源: DOAJ

【 摘 要 】

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).

【 授权许可】

Unknown