Sa1959 A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Parallel-Group Study to Assess the Effects of Teduglutide on Gastric Emptying in Healthy Subjects

Abstract

Objective: Teduglutide, a human recombinant analog of glucagon-like peptide (GLP)-2, is a novel therapy in development for short bowel syndrome. GLPs are derived fromproglucagon and, therefore, may affect gastric emptying. Change in gastric emptying may alter drug bioavailability. Our primary objective was to assess the effect of teduglutide on gastric emptying in healthy subjects, as measured by acetaminophen pharmacokinetics, an accepted measure of gastric emptying kinetics. Secondary objectives included assessment of the effects of teduglutide on preprandial and postprandial insulin, glucagon, and glucose. Methods: This double-blind, single-center study randomized 36 healthy subjects (22 male, 14 female) to receive subcutaneous doses of teduglutide 4 mg or placebo (2:1 ratio; 23:13) once daily on days 1-10 in the morning. The dose was chosen based on 0.05mg/kg/day in healthy subjects up to 80 kg in body weight. Gastric emptying was assessed by measuring acetaminophen levels pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, and 14 hours after administration of 1000 mg acetaminophen on days 0 and 10. Blood levels of glucagon, insulin, and glucose were obtained at screening, day 0, and day 10. Results: No significant differences in gastric emptying (acetaminophen area under the concentration vs time curve from time 0 to the last measureable concentration [AUC0-last], AUC0-∞, maximum concentration [Cmax]) were observed on day 10 in subjects receiving teduglutide 4 mg vs subjects receiving placebo. There was no significant difference in time to acetaminophen Cmax between the 2 groups. Similarly, there were no significant differences in preprandial or postprandial insulin level parameters (AUC0-last, AUC0-inf, Cmax, AUC0-3h, Cmax03h) between the teduglutide and placebo groups. Teduglutide increased both fasting and postprandial glucagon levels (Figure), although the differences were small and not considered clinically meaningful. Teduglutide also increased postprandial glucose up to 10 hours compared with placebo (Figure). These changes were not considered clinically meaningful (<10% increase). Conclusions: Teduglutide does not affect gastric emptying in healthy subjects as measured by acetaminophen pharmacokinetics. In healthy subjects, teduglutide did not exert any clinically meaningful effects on serum insulin, glucagon, or glucose in either the fasted or fed state.