Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults

Abstract

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced C_max and delayed T_max of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

Keywords: COVID-19; antiviral; drug-drug interaction; ensitrelvir; first-in-human; pharmacokinetics; protease inhibitor.

FIG 1

Pharmacokinetic profile of single- and multiple-dose administration of ensitrelvir and dose-proportionality following single-dose administration of ensitrelvir. Mean (SD) plasma concentration profile of ensitrelvir following administration of ensitrelvir: (A) single-dose (dose range, 20 to 2,000 mg; cohorts A–E and J) in the fasted state in Japanese healthy adult male participants (part 1); plots of (B) C_max and (C) AUC_0-inf of ensitrelvir versus dose after single-dose administration of ensitrelvir (dose range, 20–2,000 mg; cohorts A to E and J) in the fasted state in Japanese healthy adult male participants (part 1); (D) multiple-dose in the fasted state in Japanese healthy male participants (cohorts F and G); (E) multiple-dose in the fasted state in Japanese and white healthy adult male participants (cohorts F and H).

FIG 2

Effect of food on the pharmacokinetics of ensitrelvir. Mean (SD) plasma concentration profile of ensitrelvir following single-dose administration of ensitrelvir 250 mg in the fasted and fed states in Japanese healthy adult participants.

FIG 3

Drug-drug interaction. Mean (SD) plasma concentration profile of midazolam following single-dose administration of midazolam alone and coadministered with ensitrelvir on day 6.