Jiang Xiuhong, Hua Bo, Liu Gang, Xia Tian, Deng Aiyun, Lu Hui, Guo Ruoling, Wang Zhe, Liang Bo, Chen Huanming, Jin Qiu, Zhang Zhijun
Shanghai Zhimeng Biopharma, Inc, Shanghai, China.
Future Drug Development Co, Ltd, Hefei City, Anhui Province, China.
Gastro Hep Adv. 2023 Jan 7;2(4):524-531. doi: 10.1016/j.gastha.2023.01.001. eCollection 2023.
Canocapavir (ZM-H1505R) is a small-molecule hepatitis B virus capsid assembly modulator with a novel pyrazole structure. This is the first-in-human study to investigate its safety, tolerability, and pharmacokinetics (PK) following oral administration in healthy subjects.
This was a randomized, double-blind, placebo-controlled study including single ascending dose (SAD) study with an additional crossover food-effect arm, and multiple ascending dose study. In SAD, 40 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive a single dose of 25, 75, 150, 300, and 450 mg of Canocapavir or placebo in fasted state. For food-effect study, subjects in the 150 mg cohort of SAD received a second dose (150 mg) of Canocapavir in the fed state after a 7-day washout period. In multiple ascending dose, 24 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive 75, 150, and 300 mg of Canocapavir or placebo once daily for 14 days. The safety and tolerability were assessed using vital signs, physical evaluation, electrocardiogram, laboratory investigations, and adverse events (AEs). Plasma PK parameters measured included area under the curves, C, C, T, and T.
Oral administration of single doses (25-450 mg) and multiple doses (75-300 mg) of Canocapavir was well tolerated. The most common AE seen was increased alanine aminotransferase. No dose dependency was observed in incidence and intensity of AEs. Mean plasma area under the curve and C of Canocapavir increased dose-proportionally. A significant margin was observed between plasma exposure of Canocapavir and its in vitro anti-hepatitis B virus activity. Food had an effect on its absorption.
The safety and PK profile of Canocapavir support its further evaluation in chronic hepatitis B patients. The study was registered on ClinicalTrial.gov with the number NCT04220801.
卡诺卡韦（ZM-H1505R）是一种具有新型吡唑结构的小分子乙型肝炎病毒衣壳组装调节剂。这是一项在健康受试者中进行的首次人体研究，旨在调查口服给药后的安全性、耐受性和药代动力学（PK）。
这是一项随机、双盲、安慰剂对照研究，包括单剂量递增（SAD）研究及额外的交叉食物效应组，以及多剂量递增研究。在SAD研究中，40名受试者，每组8人，按3:1的比例随机分组，在禁食状态下接受单剂量25、75、150、300和450毫克的卡诺卡韦或安慰剂。对于食物效应研究，SAD研究中150毫克组的受试者在7天洗脱期后，在进食状态下接受第二剂（150毫克）卡诺卡韦。在多剂量递增研究中，24名受试者，每组8人，按3:1的比例随机分组，每天接受一次75、150和300毫克的卡诺卡韦或安慰剂，共14天。使用生命体征、体格检查、心电图、实验室检查和不良事件（AE）评估安全性和耐受性。测量的血浆PK参数包括曲线下面积、Cmax、Cmin、Tmax和Tmin。
口服单剂量（25 - 450毫克）和多剂量（75 - 300毫克）的卡诺卡韦耐受性良好。最常见的AE是丙氨酸氨基转移酶升高。未观察到AE的发生率和强度与剂量相关。卡诺卡韦的平均血浆曲线下面积和Cmax呈剂量比例增加。卡诺卡韦的血浆暴露量与其体外抗乙型肝炎病毒活性之间存在显著差异。食物对其吸收有影响。
卡诺卡韦的安全性和PK特征支持其在慢性乙型肝炎患者中进行进一步评估。该研究已在ClinicalTrial.gov上注册，注册号为NCT04220801。
