■Canocapavir(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。这是首次调查其安全性的人体研究,耐受性,和健康受试者口服给药后的药代动力学(PK)。
■这是一个随机的,双盲,安慰剂对照研究,包括单剂量递增(SAD)研究与额外的交叉食物效应臂,和多次递增剂量研究。在SAD,40个科目,每个队列中有8个,以3:1的比例随机分配,在禁食状态下接受单剂量25、75、150、300和450mg的Canocapavir或安慰剂。对于食物效应研究,在7天的清除期后,150mgSAD队列中的受试者在进食状态下接受第二剂(150mg)的Canocapavir.在多次递增剂量中,24个科目,每个队列中有8个,以3:1的比例随机接受75、150和300mg的Canocapavir或安慰剂,每天一次,共14天。使用生命体征评估安全性和耐受性,物理评估,心电图,实验室调查,和不良事件(AE)。测量的血浆PK参数包括曲线下面积,Cmax,Cmin,Tmax,和T1/2。
■口服单剂量(25-450mg)和多剂量(75-300mg)的卡诺卡韦耐受性良好。最常见的AE是丙氨酸转氨酶升高。在AE的发生率和强度中未观察到剂量依赖性。Canocapavir的曲线下平均血浆面积和Cmax剂量成比例增加。在Canocapavir的血浆暴露与其体外抗乙型肝炎病毒活性之间观察到显着的界限。食物对其吸收有影响。
■Canocapavir的安全性和PK特征支持其在慢性乙型肝炎患者中的进一步评估。该研究在ClinicalTrial.gov上注册,编号为NCT04220801。
UNASSIGNED: 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.
UNASSIGNED: 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, Cmax, Cmin, Tmax, and T1/2.
UNASSIGNED: 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 Cmax 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.
UNASSIGNED: 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.