(W0930-11-62) Disposition and Metabolism of [¹⁴C]-Tirzepatide following Subcutaneous Administration in Healthy Male Participants

Purpose: A novel GIP and GLP-1 receptor agonist, tirzepatide, is under development as a potential weekly treatment for type 2 diabetes, weight management, nonalcoholic steatohepatitis, and heart failure with preserved ejection fraction. The disposition of radioactivity, pharmacokinetics, and metabolism of a single subcutaneous (SC) dose of [¹⁴C]-tirzepatide was investigated in healthy male participants. In addition, the safety and tolerability of a single dose of [¹⁴C]-tirzepatide was also assessed.

Methods: [¹⁴C]-Tirzepatide was prepared by incorporating four ¹⁴C radiolabeled carbon atoms in the mini-PEG linker between the peptide backbone and the di-acid chain, as displayed in figure 1. A single SC injection of approximately 2.9 mg tirzepatide containing approximately 100 μCi [¹⁴C]-tirzepatide was administered to 6 healthy male participants between the ages of 30 and 56 years, inclusive. Radioactivity in plasma and excreta was measured over 42 days. After the initial 15 days of residence in the clinical research unit (CRU), participants returned to the CRU once a week for 48 hours to facilitate sparse sampling collections of plasma, urine and feces. Total radioactivity was measured in excreta, expired air, blood, and plasma. Plasma, urine, and expired air trapping solution aliquots were analyzed for radioactivity by liquid scintillation counting (LSC). Blood (whole) and feces (aqueous homogenates) were analyzed for radioactivity by combustion analysis, followed by LSC. The pharmacokinetic profile of tirzepatide in plasma was determined by a validated liquid chromatography-mass spectrometry (LC-MS) method. Metabolite identification was ascertained by LC-MS/MS, while radioprofiling was determined by fraction collection with offline radioactivity counting.

Results: Following a single SC dose of [¹⁴C]-tirzepatide, the majority ( >80%) of the excreted dose was recovered within 480 hours. Extrapolation of the data between the collection intervals of the sparse sampling resulted in an estimated overall recovery of approximately 99%. Renal excretion was identified as the principal route of elimination with approximately 66% of the administered radioactivity recovered in urine, while approximately 33% of the dose was eliminated in feces. Pharmacokinetic analysis revealed the half-life (t1/2) of tirzepatide was approximately 128 hours, while the t1/2 for total radioactivity was approximately 178 hours. Maximum concentrations of tirzepatide and total radioactivity were achieved at 24 hours post dose. Metabolite analysis of [¹⁴C]-tirzepatide revealed the parent drug was the major circulating component in plasma accounting for approximately 80% of total circulating radioactivity. Four metabolites were identified in plasma, and each individually represented less than 5.7% of the total circulating radioactivity. In urine, six metabolites were identified with two prominent metabolites accounting for 20.6% and 9.4% of the dose. The four remaining metabolites found in urine individually represented less than 3% of the dose. In feces, six metabolites were identified accounting for a total of 15.1% of the dose. Intact tirzepatide was not observed in urine or feces. Tirzepatide was primarily metabolized via proteolytic cleavage of the peptide backbone, beta-oxidation of the C20-fatty acid moiety, and amide hydrolysis. The single SC dose of [¹⁴C]-tirzepatide was well tolerated by healthy male participants. All 6 participants reported a treatment emergent adverse event (TEAE) of decreased appetite, with 1 participant also experiencing additional gastrointestinal adverse events (AEs) of nausea and vomiting. All AEs were considered mild in severity.

Conclusion: This investigation of [¹⁴C]-tirzepatide elucidated the disposition and metabolism of tirzepatide in healthy male participants. The study successfully evaluated the pharmacokinetics, total radioactivity, and metabolism of tirzepatide while simultaneously assessing the safety and tolerability of the drug.

Acknowledgements: Study funded by Eli Lilly and Company.
ClinicalTrials.gov Identifier: NCT04311424.


Figure 1. Structure of [14C]-Tirzepatide