Metabolism and disposition of 14C-retatrutide in preclinical species and humans
Mridula Dogra
Sr. Advisor-ADME Project Leadership, Eli Lilly and Company
Retatrutide is a novel synthetic molecule, which is an agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and glucagon receptor (GCGR). Phase 2 data have demonstrated up to 2.16% decrease in HbA1c from baseline to 36 weeks in patients with type 2 diabetes (Lancet 2023; 402: 529-544) and up to 24.2% weight loss in adults with a BMI of 27 kg/m2 or higher at 48 weeks (NEJM 2023; 389: 514-526). Retatrutide has a mean half-life of approximately six days, allowing for a once-weekly subcutaneous administration in humans. Although the PK of retatrutide has been evaluated in humans (Lancet 2022; 400; 1869-1881), its disposition and metabolism are not known. The current study evaluated the metabolism and disposition of 14C-radiolabeled retatrutide in preclinical species and humans. Following a single dose of 14C-retatrutide, the total recovery of radioactive dose was 94.8% by 336 hours in rats and 87.1% over 672 hours in cynomolgus monkeys. Renal excretion was the primary route of elimination in both species with 58.9% excreted in rats and 63.6% in monkeys. These data were consistent with observations in humans where the primary route of excretion was renal with about 76.7% total radioactivity in urine and 85.2% total radioactivity recovery in excreta over 1512 hours. Metabolism in preclinical species and humans was via proteolytic cleavage of the amino acid backbone, β-oxidation, oxidation and decarboxylation of the C20 fatty acid moiety and amide hydrolysis of the linker. These data show concordance and provide important information on the metabolism of retatrutide in preclinical species and humans.
AUTHORS: Mridula Dogra1, Olivier Benichou1, Shweta Urva1, Elizabeth Smith LaBell1, Mei Teng Loh1, Jennifer Gluff1, Boris Czeskis1, Kenneth Cassidy1, Ravikanth Veluri1
1Eli Lilly and Company, Indianapolis, IN, USA.
Mridula has more than 13 years of drug development experience with a unique combination of expertise ranging from formulation and drug delivery, drug metabolism, PK, and pharmacometrics. Mridula has been with Lilly since past 7+ years and has served as an ADME PL for the pre-clinical and clinical development and delivery of peptides.