A Phase I Single and Multiple Ascending Dose, Food Effect Study of the Safety, Tolerability and Pharmacokinetics of SAL0133 in Healthy Participants.

PURPOSE: SARS-CoV-2's persistent circulation and evolution necessitate development of antiviral drugs. This first-in-human Phase I study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and food effect (FE) of SAL0133, an orally bioavailable 3-chymotrypsin-like protease (3CLpro) inhibitor, in healthy participants through single ascending dose (SAD) and multiple ascending dose (MAD) parts.

METHODS

Both SAD and MAD parts were randomized, double-blind, and placebo-controlled. The SAD part included 6 dose cohorts: 50 mg (fasted), 150 mg (fasted), 300 mg (fasted); and 150 mg (fed), 300 mg (fed), 600 mg (fed). The MAD part consisted of 3 dose cohorts: 150 mg (fasted); and 150 mg (fed), 300 mg (fed), with once-daily dosing for 7 days. Participants were randomized (6:2) to receive SAL0133 or placebo. FE evaluation was integrated into both parts. Safety and tolerability were assessed throughout the study. PK parameters were analyzed using non-compartmental methods, with dose proportionality evaluated using a confidence interval (CI)-based approach. Food effects were assessed by calculating 90% CIs for geometric least squares mean ratios of ln-transformed PK parameters.

FINDINGS: SAL0133 was well tolerated. All treatment-emergent adverse events were mild except one grade 2 increased blood triglycerides. No dose-related adverse events were detected. Following a single oral administration, the median time to maximum concentration (Tmax) ranged from 3 to 6 hours, which was slightly delayed by food ingestion. Absorption saturation was reached at a single 150 mg dose under fasted conditions, while dosing after a high-fat meal significantly increased plasma maximum concentration (Cmax) by 1.89- and 3.42-fold and the area under the curve from time zero to infinity (AUCinf) by 1.45- and 3.78-fold at the 150 and 300 mg dose levels, respectively. Over the 50-150 mg dose range under fasted conditions, Cmax exhibited non-dose-proportionality, and AUC dose proportionality was inconclusive; over the 150-600 mg dose range under fed conditions, dose proportionality was also inconclusive for both AUC and Cmax, which may be partially attributable to absorptive saturation and the limited dose range under each dietary setting. Mean elimination half-lives (T1/2) ranged from 10.67 to 21.54 hours. Following multiple administrations, steady-state plasma concentrations were achieved by day 4. Under fed conditions, Cmax and AUC over the dosing interval (AUCtau) increased by approximately 1.7-fold at steady state as the dose doubled.

IMPLICATIONS: Safety and PK results support once-daily administration without CYP3A4 inhibitor co-administration. Food significantly enhances its bioavailability, suggesting that dietary conditions require strict control while dosing.