Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. The ...absorption, metabolism and excretion of a single subcutaneous (SC) dose of 14C-tirzepatide was investigated in Sprague Dawley rat and cynomolgus monkey. In addition, tissue distribution of 14C-tirzepatide was assessed in quantitative whole-body autoradiography (QWBA) study in pigmented Long Evans rat following a single SC dose.
14C-Tirzepatide was prepared by incorporating four 14C’s in the mini-PEG linker between the peptide backbone and the di-acid chain to provide a specific activity of ∼ 40 µCi/mg. Following a single SC dose of 14C-tirzepatide in rat (3 mg/kg) and monkey (0.5 mg/kg), total radioactivity recovery was > 97% over the course of study (336 hours for rat and 672 hours for monkey). The dosed radioactivity was similarly excreted via urine and feces in rats and monkeys. Metabolism of 14C-tirzepatide was characterized in plasma and excreta. Parent drug was the major component in circulation accounting for approximately 87% of total radioactivity in rat and 84% in monkey. Tirzepatide was primarily metabolized via catabolism of the peptide backbone and β-oxidation of the di-acid chain.
Following a single SC dose of 14C-tirzepatide in rats (3 mg/kg), radioactivity was distributed to tissues as early as the first collection time point at 1-hour post dose. The tissues with the highest radioactivity concentrations were observed in the dose site, kidney, cecum, urinary bladder, intervertebral ligaments, arterial wall, lungs, and liver, generally at 12 to 48 hours post dose.
Disclosure
J. Martin: Employee; Self; Eli Lilly and Company. K. Cassidy: Employee; Self; Eli Lilly and Company. B. Czeskis: None. J. Alberts: Employee; Self; Eli Lilly and Company. Y. Lao: Employee; Spouse/Partner; Eli Lilly and Company. J. Gluff: None. A.M. Niedenthal: None.
The tolerability of single daily gavage doses of 0.5% or 2.0% (wt/vol) sodium lauryl sulfate (SLS) in 11- to 12-week-old male CD-1 mice was evaluated in a study of 3 months in duration. Live-phase, ...gross necropsy, and histopathologic parameters were evaluated. Mortality of 14% occurred in mice administered formulations containing SLS. Clinical observations in mice administered SLS included abnormal respiration (audible, irregular, and/or labored), swollen abdomen, rough haircoat, hunched appearance, and hypoactivity. Necropsy findings in mice administered SLS consisted of enlarged intestines containing abnormal contents with gas. There were no instances of mechanical gavage–related injury. Histologic evaluation of the respiratory tract revealed injury to the nasal passages and nasopharynx, including, but not limited to, inflammation, exudate, apoptosis/necrosis of epithelium, and atrophy of epithelium or olfactory nerves. Collectively, the data indicated that under the experimental conditions of our 3-month study in male CD-1 mice, once-daily gavage administration of vehicle formulations containing SLS at 0.5% or 2.0% resulted in nasal injury and 14% mortality supportive of gastroesophageal reflux. Sponsors utilizing formulations containing SLS in toxicity studies in CD-1 mice should exclude gastroesophageal reflux as a confounding factor in studies with morbidity or mortality associated with respiratory distress or evidence of aerophagia.
