AUTHOR=Xu Su-Mei , Chang Li-Wen , Tsai Cheng-Yuan , Liu Wan-Li , Li Dai , Li Shan-Shan , Li Xiao-Min , Xu Ping-Sheng 

TITLE=Safety, tolerability, and pharmacokinetics of TG-1000, a new molecular entity against influenza virus: first-in-human study

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1272466

DOI=10.3389/fphar.2023.1272466

ISSN=1663-9812

ABSTRACT=Background: The cap-snatching mechanism of influenza virus mRNA transcription is strongly suppressed by TG-1000, a prodrug rapidly metabolized into TG-0527, is a potent cap-dependent nucleic acid endonuclease inhibitor. Herein, we aimed to assess the safety, tolerability, and pharmacokinetics of TG-1000 in healthy participants and the effect of food on the pharmacokinetics and safety of TG-1000.
Method: The study was divided into 2 parts: Part A (Single Ascending-Dose (SAD) study, 10-160 mg) and Part B (Food-Effect (FE) study, 40 mg) were launched sequentially. The study included 66 participants for both investigations. We administered different TG-1000 capsules or placebo doses per the study protocol and collected blood samples for pharmacokinetic assessments at specific times. In plasma, TG-1000 and its active metabolite TG-0527 were assayed, and PK parameters were determined. 
Results: In SAD, the increase in AUC was less than the proportional increase in dose over the 20-160 mg dose range, while the increase in Cmax was proportional to the increase in dose. In the 10-160 mg dose range, T1/2, λz and Tmax of TG-0527 were dose-independent; and T1/2 and Tmax were within 33.8-39.4 h and 3.02-6 h, respectively. In FE, the AUC0-inf, AUC0-last, and Cmax of TG-0527 decreased by approximately 17.52%, 18.76%, and 41.35%, respectively, and the Tmax delay was around 1.50 hours. No serious adverse events occurred during the studies.
Conclusion: Overall, TG-1000 was well tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of TG-1000 for the treatment of influenza.