Population Pharmacokinetics of an Extended-Release Formulation of Exenatide Following Single- and Multiple-Dose Administration

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.