title: 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.
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.
authors.affiliation: Amylin Pharmaceuticals, Inc., San Diego, California 92121, USA. jaret.malloy@amylin.com
authors.forename: Jaret
authors.initials: J
authors.lastname: Malloy
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Michael
authors.initials: M
authors.lastname: Gottschalk
authors.forename: Xuesong
authors.initials: X
authors.lastname: Guan
authors.forename: Prajakti
authors.initials: P
authors.lastname: Kothare
authors.forename: Mark
authors.initials: M
authors.lastname: Fineman
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D002648:Child; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019518:Postprandial Period; D016037:Single-Blind Method; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide