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

Clin Ther. 2009 Apr;31(4):806-15. doi: 10.1016/j.clinthera.2009.04.005.

Abstract

Objective: 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 dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 microg, exenatide 5 microg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 microg always preceded exenatide 5 microg 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 microg, 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-microg dose; after administration of exenatide 2.5-microg, 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 pg, -4422.2 (2434.4) mg * min/dL for exenatide 5 microg, 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-microg doses of exenatide were associated with dose-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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Area Under Curve
  • Blood Glucose / drug effects
  • Child
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Exenatide
  • Female
  • Glucagon / blood
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology*
  • Injections, Subcutaneous
  • Insulin / blood
  • Male
  • Peptides / administration & dosage
  • Peptides / adverse effects
  • Peptides / pharmacology*
  • Postprandial Period
  • Single-Blind Method
  • Venoms / administration & dosage
  • Venoms / adverse effects
  • Venoms / pharmacology*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Venoms
  • Glucagon
  • Exenatide

Associated data

  • ClinicalTrials.gov/NCT00254254