Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing

Clin Pharmacokinet. 2011 Jan;50(1):65-74. doi: 10.2165/11585880-000000000-00000.


Background and objectives: Exenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus.

Patients and methods: Patients with type 2 diabetes participated in either a single-dose trial (n = 62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.

Results: Exenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6-7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (-42.7 ± 15.7 mg/dL with the 0.8 mg dose and -39.0 ± 9.3 mg/dL with the 2 mg dose; both p < 0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC(50)) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2 mg doses of exenatide ER). The 2 mg dose reduced bodyweight (-3.8 ± 1.4 kg; p < 0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbA(1c)) levels were reduced with the 0.8 mg dose (-1.4 ± 0.3%; baseline 8.6%) and with the 2 mg dose (-1.7 ± 0.3%; baseline 8.3%) [both p < 0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity.

Conclusion: These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [ Identifier: NCT00103935].

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose
  • Delayed-Action Preparations
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Exenatide
  • Gastric Emptying / drug effects
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / pharmacokinetics
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Peptides / pharmacokinetics*
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Receptors, Glucagon / agonists
  • Venoms / pharmacokinetics*
  • Venoms / pharmacology*
  • Venoms / therapeutic use


  • Blood Glucose
  • Delayed-Action Preparations
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide

Associated data