Continuous Intravenous Administration of Teduglutide (ALX-0600), a Glucagon-like Peptide-2 (GLP-2) Analog Induces Intestinotrophic Activity

Abstract

Purpose: Teduglutide is an analog of human GLP-2, a naturally occurring peptide secreted from endocrine L cells predominantly in the distal intestine. Teduglutide has been shown to increase intestinal mass as a result of increased villus height and crypt depth. In preclinical rodent models, subcutaneous administration of teduglutide augments the adaptive response following small bowel resection and reduces the deleterious effects of IBD-related and chemotherapy-induced intestinal damage. This study compared the intestinotrophic effects of continuous intravenous to daily subcutaneous administration of teduglutide in rat. Methods: Female Sprague Dawley rats were administered teduglutide either by continuous intravenous infusion (0.5 mg/kg/day) or subcutaneous injection (0.5 mg/kg/day, b.i.d.) for 14 days. Morphological changes, including intestinal weight and length, were used to measure changes in the gastrointestinal tract. Results: Small and large intestinal weights increased significantly, by 125% and 35% respectively, in animals treated with teduglutide by continuous infusion. Small intestinal weight increased significantly by 88% and a trend towards increased large intestinal weight was observed in animals receiving teduglutide by subcutaneous injection. A trend towards increased small intestinal length was observed in both treatment groups, however, this effect only reached statistical significance in animals administered teduglutide by continuous infusion. Increased villus height was observed in the small intestine in animals given teduglutide intravenously and in the small and large intestine in animals given teduglutide subcutaneously. The pharmacokinetics following intravenous infusion of teduglutide were predictable and the steady-state plasma concentration of teduglutide was maintained throughout the 14 days of dosing (40.2 ± 8.8 ng/mL on Day 2 and 50 ± 30.8 ng/mL on Day 14). The total daily exposure to teduglutide was higher in the intravenous group (965–1200 ng-h/mL) than in the group receiving the same dose of teduglutide by subcutaneous injection (682 ng-h/mL). Conclusion: Administration of teduglutide by continuous intravenous infusion or subcutaneous injection was associated with increased intestinal weights and intestinal mucosal mass. Plasma concentrations after continuous intravenous infusion of teduglutide were well predicted. These results suggest that continuous systemic and intermittent exposure to teduglutide give similar pharmacological responses.