TLR7激动剂前药RO6870868在健康志愿者中的安全性，耐受性，药

StephenW

Safety, tolerability, pharmacokinetics and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers
Joseph F Grippo  1 , Ilia Folitar  2 , Sharon Passe  1 , Qiudi Jiang  3 , Ignacio Rodriguez  1 , Scott H Fettner  1 , Elizabeth Calleja  1
Affiliations
Affiliations

    1
    Roche Innovation Center New York, United States.
    2
    Roche Innovation Center, Basel, Switzerland.
    3
    Roche Innovation Center Shanghai, Shanghai, China.

    PMID: 33742764 DOI: 10.1111/cts.13016

Abstract

RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO6870868 in a first-in-human, phase 1, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200 mg-2000 mg). Single oral doses were generally well tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events were reported and no subject withdrew from the study due to an adverse event. No clinically significant changes were observed in vital signs, electrocardiograms or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 hours across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0-∞ ) increasing proportionally with dose. A pattern of dose- and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Keywords: Immune Response; Pharmacodynamics; Pharmacokinetics; Prodrug; TLR7.

This article is protected by copyright. All rights reserved.

StephenW

TLR7激动剂前药RO6870868在健康志愿者中的安全性，耐受性，药代动力学和药效学
Joseph F Grippo 1，Ilia Folitar 2，Sharon Passe 1，Jiandi Jiang 3，Ignacio Rodriguez 1，Scott H Fettner 1，Elizabeth Calleja 1
隶属关系
隶属关系

    1个
    美国纽约罗氏创新中心。
    2个
    瑞士巴塞尔罗氏创新中心。
    3
    上海罗氏创新中心，中国上海。

    PMID：33742764 DOI：10.1111 / cts.13016

抽象的

RO6870868是Toll样受体7（TLR7）特异性激动剂RO6871765的口服前药。 TLR7激动剂可增强宿主的免疫活性，并且正在开发中以治疗乙型肝炎感染。我们在60例健康志愿者中以6种剂量水平（200 mg-2000 mg）进行了首次人类首次1期随机，单次递增口服剂量研究，评估了RO6870868的安全性，耐受性，药代动力学（PK）和药代动力学（PD）。 ）。一般而言，单次口服剂量耐受性良好，可预测的安全性与全身性干扰素的剂量依赖性增加有关。没有报告严重的不良事件，也没有受试者因不良事件而退出研究。在生命体征，心电图或实验室参数方面未观察到临床上的显着变化。口服RO6870868剂量后，血浆RO6871765浓度迅速增加，在所有队列中均表现出2-6小时的平均终末半衰期，血浆浓度与时间的关系曲线下的面积外推至无穷大（AUC0-∞）与剂量成比例增加。证实了剂量和时间依赖性PD活性的模式与TLR7系统的参与一致。单个RO6870868以剂量依赖的方式对TLR先天性免疫系统的激活成分进行剂量测定，并具有足够的安全性和耐受性。健康志愿者的单剂量数据可用于评估TLR7激动剂的安全性，PK和PD活性，并有助于指导剂量和方案选择，以用于慢性乙型肝炎患者的进一步试验。

关键字：免疫反应；药效学；药代动力学；前药； TLR7。

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StephenW

https://ascpt.onlinelibrary.wile ... t/10.1111/cts.13016

lancas

又有新药可以临床了