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

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. The single ascending dose (SAD) part 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 was a randomised, two-cycle, two-way crossover design, which enrolled 16 participants to receive single oral dose of 80 mg ZX-7101A tablets. 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 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 AUC0-24 was 1655.4 to 11483.7 h*ng/mL. The FE part showed the high-fat meal significantly affected the exposure parameters compared to the fasted condition. The Cmax and AUC0-t of ZX-7101 under fasted condition were 1.73 and 1.78 times those under fed condition, respectively. 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).