Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.

Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-blind study consisting of four components: a single ascending dose study, a drug-drug interaction study, a multiple ascending dose study, and a food-effect study. All participants were randomly assigned to receive either a single dose or multiple doses of RAY1216 or placebo. A total of 88 healthy adult participants (male-to-female ratio of 1:1) aged 18-50 years were enrolled. A total of 37 participants (42%) experienced at least one adverse event (AE). All AEs were mild or moderate and were resolved without additional treatment. The most commonly reported adverse drug reactions were hypertriglyceridemia, hyperuricemia, and elevated serum creatinine levels. RAY1216 was well-absorbed after administration with exposure increasing in a dose-dependent manner. Food appeared to increase exposure and delay the absorption of RAY1216. Ritonavir significantly inhibited drug metabolism, and increased drug exposure increased the associated safety risks. RAY1216 was found to be well tolerated and safe in healthy participants. On the basis of preclinical results, PK characteristics, and the safety profile of RAY1216, a dosage of 400 mg three times daily was selected, thereby establishing a foundation for future research and for the clinical application of RAY1216.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05829551.