Population pharmacokinetics of exenatide.
AIM
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.


METHODS
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.


RESULTS
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-1 and 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.


CONCLUSIONS
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.
['Cirincione|Brenda|B|', 'Mager|Donald E|DE|']
D000293:Adolescent D000328:Adult D000368:Aged D002986:Clinical Trials as Topic D003198:Computer Simulation D004305:Dose-Response Relationship, Drug D000077270:Exenatide D005260:Female D006801:Humans D007004:Hypoglycemic Agents D008297:Male D008875:Middle Aged D008954:Models, Biological D017711:Nonlinear Dynamics D010455:Peptides D014688:Venoms D055815:Young Adult
pharmacokinetics exenatide renal impairment type 2 diabetes mellitus