Pharmacology and Tolerability of a Single Dose of Exenatide in Adolescent Patients With Type 2 Diabetes Mellitus Being Treated With Metformin: A Randomized, Placebo-Controlled, Single-Blind, Dose-Escalation, Crossover Study

Obiective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM). Methods: This was a randomized, single-blind, dose-escalation, Crossover Study in adolescent (age 10-16 years) patients with T2DM who were being treated with diet and exercise or a stable close of metformin, a Sulfonylurea, or a combination of metformin and a sulfonylurea for at least 31 months before screening. Eligible patients were allocated to receive single subcutaneous closes of exenatide 2.5 mu g, exenatide 5 mu g, and placebo, each followed by a standardized meal, on 3 separate days (maxiimum interval between first and third closes, 5 weeks). Exenatide 2.5 mu g always preceded exenatide 5 mu g in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations. Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean [SD] age, 15 [1] years; body mass index, 32.5 [5.0] kg/m(2); glycosylated hemoglobin, 8.2% [1.5%]). After administration of exenatide 5 mu g, the geometric mean (SE) exenatide AUC(0-infinity) and C-max were 339.5 (39.6) pg . h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-mu g dose; after administration of exenatide 2.5 mu g, the geometric mean AUC(0-infinity) was 159.2 (23.1) pg . h/mL, (n = 6) and the geometric mean C-max was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandial plasma glucose excursions compared with placebo (P < 0.01); the incremental mean (SE) AUC(15-360min) was -3465.6 (1587.3) mg . min/dL for exenatide 2.5 mu g, -4422.2 (2434.4) mg . min/dL for exenatide 5 mu g, and 3457.4 (1615.5) mg - min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo (P < 0.01); the respective Incremental mean values for AUC(15-180min) were 125.5 (658.4), -1403.8 (632.1), and 1843.1 (540.6) pg . min/mL. There were no significant differences in serum Insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic: events recorded during the study. Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-mu g doses of exenatide were associated with close-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254. (Clin Ther. 2009;31:806-815) (C) 2009 Excerpta Medica Inc.