Abstract
Exenatide is a glucagon-like peptide-1 receptor agonist with both immediate- and extended-release (ER) formulations that are approved for the treatment of type 2 diabetes mellitus. Long-term exposure from the ER formulation is achieved through slow peptide release from a degradable microsphere formulation. The goal of this analysis was to develop a pharmacokinetic model for the ER formulation following single and once-weekly multiple-dose administration. Pharmacokinetic data were collected from two clinical trials—one that evaluated single-dose administration of 2.5, 5, 7, and 10 mg of ER exenatide and a second that included weekly administration of 0.8 and 2 mg for 15 weeks. A population pharmacokinetic model, describing 1586 exenatide concentrations from 64 patients, was developed in the nonlinear mixed-effects modeling software program NONMEM. Pharmacokinetics of the ER formulation was described by a two-compartment model with linear and nonlinear elimination. The complex absorption profile was quantified using three simultaneous processes: a first-order process characterizing a rapid initial release and two series of transit compartments to describe the second (∼3 weeks postinjection) and third phases of drug release (∼7 weeks postinjection). Estimation of the combined single- and multiple-dose data adequately described the rise to steady-state (∼8–10 weeks) and decline to undetectable concentrations that occurred about 10 weeks after treatment cessation. Thus, a population-based pharmacokinetic model was developed that provides a platform for future pharmacodynamic analyses with the ER formulation of exenatide.
Highlights
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that has been shown to improve glycemic control among patients with type 2 diabetes mellitus [1, 2]
The first study was a phase II, randomized, double-blind, placebo-controlled 12-week trial in patients with type 2 diabetes using a single dose of the ER formulation at doses of 2.5, 5, 7, and 10 mg, which resulted in measurable exenatide concentrations for approximately 9–11 weeks postinjection [18]
The sustained release of exenatide was achieved by the dispersion of exenatide within PLGA microspheres, such that the active peptide that is released and absorbed into the circulation following SC administration is identical to that found in the IR formulation [17]
Summary
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that has been shown to improve glycemic control among patients with type 2 diabetes mellitus [1, 2]. The exenatide peptide elicits its glycemic response through multiple mechanisms of action, Electronic supplementary material The online version of this article (doi:10.1208/s12248-016-9975-1) contains supplementary material, which is available to authorized users. A retrospective population PK analysis describing a wide range of exenatide concentrations associated with multiple routes of administration identified significant covariates that influence systemic exposure of the IR formulation, including renal function on systemic clearance and body weight on the volume of distribution The IR formulation is administered twice daily, within 60 min prior to the morning and evening meals, to achieve effective daily glycemic control [1]. In order to improve patient compliance and further improve glycemic benefit, new drug formulations are under development with the
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call