Pharmacokinetic and mass balance characterization of [ 14 C] RAY1216, a SARS-CoV-2 M pro inhibitor, in healthy Chinese male subjects

Background RAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (M pro ). This study evaluated the absorption, distribution, metabolism and excretion of [ 14 C]-labelled RAY1216 by oral administration. Research design and methods This phase Ι study was designed to assess the pharmacokinetics, mass balance and metabolic pathways in 6 healthy Chinese adult men after a single fasting oral administration of 240 mL (containing 400 mg/100 μCi) [ 14 C] RAY1216. Results RAY1216 absorbed rapidly in the plasma, with a C max of 1796.83 ng/mL, t max of 1.42 h and t 1/2 of 5.97 h. RAY1216 is mainly excreted through feces and a small amount through urine, indicating that the excretion of RAY1216 occurs through the fecal route, within 96 h after administration, the majority (>90%) of the radioactive substances were excreted 104.17% of the metabolites were identified in urine and fecal samples. The radioactive transformation pathways suggest that RAY1216 has multiple metabolic pathways, including Oxidation-dealkylation, Mono-oxidation, Hydrolysis, and Urea binding. There were no reports of death, serious adverse events (SAEs), or withdrawals related to SAEs. Conclusion The overall recovery rate data of radioactive substances in the excreta of all 6 subjects indicate that favourable mass balance recovery. The overall safety profile is favourable, and it demonstrates promising potential in mitigating both the duration and severity of COVID-19, and the comprehensive clinical safety and therapeutic effect are significantly superior to those of similar COVID-19 treatment drugs. RAY1216 can be referred to and further verified for the Phase II and Phase III clinical trials for the treatment of COVID-19.