在健康受试者中单次或多次递增剂量后，评估人体中五项合

StephenW

A five-in-one first-in-human study to assess safety, tolerability, and pharmacokinetics of RO7049389, an inhibitor of hepatitis B virus capsid assembly, after single and multiple ascending doses in healthy participants
Sheng Feng  1 , Edward Gane  2 , Christian Schwabe  2 , Mingfen Zhu  3 , Miriam Triyatni  4 , Julian Zhou  5 , Qingyan Bo  3 , Yuyan Jin  6
Affiliations
Affiliations

    1
    Pharmaceutical Sciences, Roche Innovation Center Shanghai, Shanghai, China.
    2
    Auckland Clinical Studies, Auckland, New Zealand.
    3
    I2O DTA, Roche Innovation Center Shanghai, Shanghai, China.
    4
    Early Development Safety, Roche Innovation Center Basel, Basel, Switzerland.
    5
    Biostatistics, Roche Pharma Product Development Shanghai, Shanghai, China.
    6
    Pharmaceutical Sciences, Roche Innovation Center Shanghai, Shanghai, China. [email protected].

    PMID: 32839221 DOI: 10.1128/AAC.01323-20

Abstract

RO7049389, an inhibitor of hepatitis B virus (HBV) capsid assembly, is being developed for the treatment of patients with chronic HBV infection. The objectives of this first-in-human study are to assess the safety, tolerability, pharmacokinetics (PK), food effect, inhibitory effect on CYP3A, and effect on QT of RO7049389 in healthy participants. Five components, single ascending doses (SAD) cohorts, multiple ascending doses (MAD) cohorts, food effect assessment, drug-drug interaction assessment, and concentration-QT analysis were integrated in one study (five-in-one). Participants randomly received a single dose of 150-2500 mg RO7049389 or placebo in SAD cohorts (n = 41), or multiple doses of 200-800 mg RO7049389 or placebo in MAD cohorts (n = 42). A single doses of 450 mg RO7049389 was administrated under fasted and fed condition. The micro-dose of midazolam was administrated before and after multiple dosing of RO7049389. Safety and tolerability were monitored throughout the study. Serial blood and urine samples were collected for the PK analysis. RO7049389 was safe and well tolerated in healthy participants. Absorption and elimination of RO7049389 occurred rapidly in plasma with minimal recovery in urine. Greater than dose-proportional increases in plasma exposure were observed. Exposure of RO7049389 (450 mg) increased by ∼2 fold when administered with a high fat meal. The inhibition effect of RO7049389 on CYP3A was weak (< 20%). No effect on QT interval was observed up to a single dose of 2500 mg. RO7049389 displayed a favorable safety, tolerability and PK profile suitable for further clinical development.

Copyright © 2020 American Society for Microbiology.

StephenW

在健康受试者中单次或多次递增剂量后，评估人体中五项合一的首次研究，评估乙肝病毒衣壳装配抑制剂RO7049389的安全性，耐受性和药代动力学
盛丰1，爱德华·加恩2，克里斯汀·施瓦贝2，朱明芬3，米里亚姆·特里亚尼4，朱利安·周5，青青波3，金玉妍6
隶属关系
隶属关系

    1个
    药物科学，上海罗氏创新中心，中国上海。
    2
    奥克兰临床研究，新西兰奥克兰。
    3
    I2O DTA，上海罗氏创新中心，中国上海。
    4
    瑞士巴塞尔罗氏创新中心的早期开发安全部。
    5
    罗氏制药产品开发有限公司，上海，生物统计。
    6
    药物科学，上海罗氏创新中心，中国上海。 [email protected]。

    PMID：32839221 DOI：10.1128 / AAC.01323-20

抽象

RO7049389是乙型肝炎病毒（HBV）衣壳装配的抑制剂，目前正在开发中，用于治疗慢性HBV感染的患者。这项首次人类研究的目的是评估健康受试者的安全性，耐受性，药代动力学（PK），食物效应，对CYP3A的抑制作用以及对RO7049389的QT的影响。一项研究（五合一）整合了五个组成部分，即单次递增剂量（SAD）队列，多次递增剂量（MAD）队列，食物效果评估，药物-药物相互作用评估和浓度-QT分析。参与者在SAD队列中随机接受单剂量150-2500 mg RO7049389或安慰剂（n = 41），或在MAD队列中随机接受200-800 mg RO7049389或安慰剂的多剂量（n = 42）。在禁食和进食条件下单剂量服用450 mg RO7049389。多次给药RO7049389之前和之后都应服用咪达唑仑的微剂量。在整个研究过程中对安全性和耐受性进行了监测。收集连续的血液和尿液样本进行PK分析。 RO7049389是安全的，对健康参与者的耐受性良好。 RO7049389的吸收和消除在血浆中迅速发生，尿液回收率最低。观察到血浆暴露大于剂量比例增加。与高脂餐一起服用时，RO7049389（450毫克）的暴露量增加了约2倍。 RO7049389对CYP3A的抑制作用较弱（<20％）。直至单次剂量2500 mg，未观察到对QT间隔的影响。 RO7049389显示出良好的安全性，耐受性和PK谱，适用于进一步的临床开发。

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