title: Population Pharmacokinetics of an Extended-Release Formulation of Exenatide Following Single- and Multiple-Dose Administration.
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.
authors.affiliation: Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey, 08543-4000, USA. brenda.cirincione@bms.com.|Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA. brenda.cirincione@bms.com.
authors.forename: Brenda
authors.initials: B
authors.lastname: Cirincione
authors.affiliation: Amylin Pharmaceuticals, San Diego, California, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000077270:Exenatide; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D014688:Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: exenatide; pharmacokinetics; subcutaneous extended release; transit compartments; type 2 diabetes mellitus