Disposition and Absolute Bioavailability of Orally Administered Orforglipron in Healthy Participants

Abstract Orforglipron is a non‐peptide, oral glucagon‐like peptide 1 receptor agonist under development for glycemic control in adults with type 2 diabetes and weight management in people with obesity. Two phase 1, open‐label studies evaluated the disposition and absolute bioavailability of orforglipron in healthy adults. Study A participants (N = 10) received a 1‐mg orforglipron oral capsule while fasting and an intravenous dose of ∼21 µg of [14C]‐orforglipron. Study B participants (N = 6) received an oral solution of 3 mg of orforglipron with ∼200 µCi of [14C]‐orforglipron while fasting. In study A, total plasma radioactivity and [14C]‐orforglipron were measured by accelerator mass spectrometry (AMS) and high‐performance liquid chromatography (HPLC)/AMS, while orforglipron was measured by HPLC/MS. The mean absolute oral bioavailability of orforglipron was 79.1% ± 16.8%. In study B, urine and feces were analyzed for total radioactivity. Metabolic radioprofiling was performed on selected plasma and fecal samples by HPLC/high‐resolution MS. The primary route of elimination for [14C]‐orforglipron‐related radioactivity was via the feces (87% ± 2.8%) with minimal urinary excretion (0.2% ± 0.02%). Total recovery of administered radioactivity was 88% over 384 hours after the dose. Metabolite profiling from study B showed that orforglipron underwent extensive oxidative metabolism, followed by microbial metabolism of the oxadiazolone ring. Orforglipron was the most abundant plasma component (93.3%) with minor oxidative metabolites M7 (3.3%) and M23 (1.6%).