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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.

Author information

1
Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey, 08543-4000, USA. brenda.cirincione@bms.com.
2
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA. brenda.cirincione@bms.com.
3
Amylin Pharmaceuticals, San Diego, California, USA.
4
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.

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.

KEYWORDS:

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

PMID:
27896683
DOI:
10.1208/s12248-016-9975-1
[Indexed for MEDLINE]

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