Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects

BACKGROUND AND OBJECTIVE: Glepaglutide is a novel, long-acting, glucagon-like peptide-2 analogue in a stable aqueous formulation for subcutaneous dosing to treat patients with short bowel syndrome. This study was conducted primarily to characterise the pharmacokinetics of glepaglutide in healthy subjects. METHODS: In this open-label, partially randomised, parallel-group study, healthy subjects were evenly randomised to glepaglutide 5 or 10 mg dosed subcutaneously once weekly for 6 weeks or to a single intravenous infusion of glepaglutide 1 mg. Each group comprised 15 subjects. Blood samples were drawn to determine plasma concentrations of the parent drug and its two main metabolites. Concentrations of glepaglutide were calculated as the sum of these three analytes. Citrulline was included as a pharmacodynamic biomarker. Safety was assessed throughout the study. RESULTS: From a comparison of pharmacokinetic parameters following subcutaneous versus intravenous dosing, it is concluded that the pharmacokinetics of glepaglutide following subcutaneous dosing are primarily determined by slow release of the two main glepaglutide metabolites from a subcutaneous depot. For subcutaneous dosing once weekly, the two main metabolites accounted for >98% of the overall glepaglutide exposure at steady state, with the parent drug contributing to less than 1% of exposure. The estimated mean (95% confidence interval) effective half-life for glepaglutide 5 and 10 mg was 124 (73–185) h and 88 (31–146) h, respectively. There was an increase in the citrulline concentration for both glepaglutide subcutaneous dose levels. No safety issues were identified. CONCLUSIONS: Slow release of active metabolites following subcutaneous dosing leads to a significantly protracted pharmacokinetic profile for glepaglutide. These results support that once- or twice-weekly subcutaneous dosing of glepaglutide could be an efficacious therapy for intestinal rehabilitation. CLINICALTRIALS.GOV IDENTIFIER: NCT03279302. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40261-022-01210-1.