Evaluation of the safety, tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers

Xiaojie Wu, Sheng Feng, Jing Zhang, Wenhong Zhang, Yuchen Zhang, Mingfen Zhu, Miriam Triyatni, Na Zhao, Qingyan Bo, Yuyan Jin, Xiaojie Wu, Sheng Feng, Jing Zhang, Wenhong Zhang, Yuchen Zhang, Mingfen Zhu, Miriam Triyatni, Na Zhao, Qingyan Bo, Yuyan Jin

Abstract

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first-in-human study (in which most of the HVs were non-Asian). HVs randomly received a single dose of 200-600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200-400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well-tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half-life ranged from 3.66 to 14.6 h. A single dose of 200-600 mg and multiple doses of 200-400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non-Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non-Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.

Trial registration: ClinicalTrials.gov NCT03570658.

Conflict of interest statement

X.W., J.Z., and W.Z. are full‐time employees of Huashan Hospital. Y.Z., M.T., N.Z., Q.B., and Y.J. are full‐time employees of F. Hoffmann‐La Roche. S.F. and M.Z. were previously a full‐time employee of F. Hoffmann‐La Roche during this work.

© 2021 Roche R&D Center China Ltd. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1
FIGURE 1
Overview of the study design. PK, pharmacokinetic.
FIGURE 2
FIGURE 2
Mean (±SD) plasma concentration (Conc)‐time curves of RO7049389 and its three metabolites after single doses of RO7049389 in healthy volunteers (semilog)
FIGURE 3
FIGURE 3
Mean (±SD) plasma concentration (Conc)‐time curves of RO7049389 and its three metabolites after multiple doses of RO7049389 in healthy volunteers (semilog)

References

    1. WHO Fact Sheet N°204, updated July 2019. . Accessed May 8, 2020.
    1. European Association for the Study of the Liver . EASL 2017 clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2017;67:370‐398.
    1. Zhou X, Zhou Y, Tian X, et al. In vitro and in vivo antiviral characterization of RO7049389, a novel small molecule capsid assembly modulator for the treatment of chronic hepatitis B. J Hepatol. 2018;68:S770.
    1. Feng S, Gane E, Schwabe C, et al. 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. Antimicrob Agents Chemother. 2020;64(11):e01323‐e01420.
    1. Cosson V, Feng S, Jaminion F, et al. How semiphysiological population pharmacokinetic modeling incorporating active hepatic uptake supports phase II dose selection of RO7049389, a novel anti–hepatitis B virus drug. Clin Pharmacol Ther. 2021;109(4):1081‐1091.
    1. Tomita Y, Maeda K, Sugiyama Y. Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG‐CoA reductase inhibitors: a kinetic consideration of its mechanism. Clin Pharmacol Ther. 2013;94(1):37‐51.

Source: PubMed

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