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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. |
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