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AAPS J. 2017 Mar;19(2):487-496. doi: 10.1208/s12248-016-9975-1. Epub 2016 Nov 28.

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

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Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey, 08543-4000, USA.
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
Amylin Pharmaceuticals, San Diego, California, USA.
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.


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.


exenatide; pharmacokinetics; subcutaneous extended release; transit compartments; type 2 diabetes mellitus

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