Safety, Tolerability, and Pharmacokinetics of a Novel Anti-Influenza Agent ZX-7101A Tablets in Healthy Chinese Participants: A First-in-Human Phase I Clinical Study.

Background: We investigated the safety, tolerability, and pharmacokinetics of ZX-7101A tablets, a novel cap-dependent endonuclease inhibitor, in healthy participants in a first-in-human study.

Methods: The single ascending dose (SAD) part of the study included 40, 80, 160, 240, and 320 mg dose cohorts with10 participants in each dose cohort (8 participants received ZX-7101A tablets and 2 participants received placebo). The food effect (FE) part of the study was a randomised, 2-cycle, 2-way crossover design, which enrolled 16 participants to receive a single oral dose of 80 mg ZX-7101A tablets.

Results: ZX-7101A tablets were safe and well-tolerated in both SAD and FE studies. No participant died or experienced SAE, or withdrew prematurely. The prodrug ZX-7101A was rapidly transformed into the active ingredient ZX-7101 after a single oral dose of 40-320 mg. The blood concentration of ZX-7101A was below the lower limit of quantification at most time points. ZX-7101 reached peak concentration about 3-4 h postdose in all dose cohorts. The elimination half-life of ZX-7101 was 83.01-125.55 h, and AUC_0-24 was 1655.4-11483.7 h*ng/mL. The FE part showed that the high-fat meal significantly affected the exposure parameters compared to the fasted condition. The C_max and AUC_0-t of ZX-7101 under the fasted condition were 1.73 and 1.78 times those under the fed condition, respectively.

Conclusions: A single oral dose of 40 mg and 80 mg ZX-7101A tablets achieved sufficient ZX-7101 exposure for effectively inhibiting influenza A and B viruses and avian influenza viruses. These findings support 40 mg and 80 mg of ZX-7101A tablets as single dose regimens for use in phase II/III clinical trials. This study was registered at chinadrugtrials.org.cn (identifier: CTR20212778).