Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [¹⁴C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [¹⁴C]-Tirzepatide was prepared by incorporating four ¹⁴C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 μCi of [¹⁴C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg^-1 (133 µCi/kg) of [¹⁴C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg^-1 (20 µCi/kg) of [¹⁴C]-tirzepatide. Following a single SC dose of [¹⁴C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, β-oxidation of the C20 diacid moiety, and amide hydrolysis. ClinicalTrials.gov identifier: NCT 04,311,424.