Study of the mass balance, biotransformation, and safety of ¹⁴CIBI351 in healthy Chinese subjects

IBI351, a synthetic compound, exerts its anti-tumor effects by specifically, covalently, and irreversibly modifying the 12th cysteine residue of KRAS G12C. However, the pharmacokinetic characteristics of IBI351 in the human body have not been reported. The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects. A single oral dose of 600 mg/150 μCi ¹⁴CIBI351 was administered to six healthy male subjects. Blood, urine, and fecal samples were collected at continuous time points to analyze the levels of IBI351 parent drug and its metabolites. We found that IBI351 showed favorable pharmacokinetic characteristics, and was well tolerated in all the six participants. In addition, 17 major metabolites of IBI351 were analyzed and identified in the blood, urine, and feces. The main metabolic pathways included oxidation, hydrogenation, sulfonate conjugation, glucuronide conjugation, and cysteine conjugation. IBI351 and its metabolites were primarily excreted through feces. Taken together, this is the first study on the metabolism and safety of IBI351 in Chinese subjects, and these findings may guide future clinical development of IBI351 as a novel anti-tumor drug.