title: Population pharmacokinetics of exenatide.
abstract: The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate-release (IR) exenatide, which can be used in subsequent analyses of novel sustained-release formulations.
  
  
  
  Data from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed-effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks.
  
  
  
  The pharmacokinetics of IR exenatide was described by a two-compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero-order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr-1. The nonlinear elimination was quantified with a Michaelis-Menten constant (Km) of 567 pg ml-1and a maximum rate of metabolism (Vmax) of 1.6 μg h-1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero-order process, and the remaining 63% via the nonlinear pathway.
  
  
  
  The present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained-release exenatide formulations.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA.|Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Cirincione
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010455:Peptides / Q000493:pharmacokinetics*; D014688:Venoms / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: exenatide; pharmacokinetics; renal impairment; type 2 diabetes mellitus