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.

Impact on HbA1c and body weight of switching from other GLP‐1 receptor agonists to semaglutide: A model‐based approach

“…The following strategy was applied to predict the HbA1c and body weight time courses when switching from another GLP‐1RA to semaglutide. (1) Published PK models were used to predict the exposure time‐course of liraglutide, dulaglutide, exenatide ER and semaglutide for exposure response modelling, including potential switch scenarios . (2) Time‐course exposure‐response models for semaglutide were developed based on data from the SUSTAIN trials (Figure and Table S1).…”

“…For the analysis of exenatide ER, which was compared with semaglutide in the SUSTAIN 3 phase 3 trial, we applied a clinical pharmacology population PK model, using data from previous trials with single‐dose administration of 2.5, 5, 7 and 10 mg of exenatide ER or weekly doses of 0.8 and 2.0 mg in subjects with T2DM …”

“…(1) Published PK models were used to predict the exposure time-course of liraglutide, dulaglutide, exenatide ER and semaglutide for exposure response modelling, including potential switch scenarios. [18][19][20][21] (2) Time-course exposure-response models for semaglutide were developed based on data from the SUSTAIN trials ( Figure 1 and Table S1). For the analysis of liraglutide, which was compared with semaglutide in the phase 2 trial, 17 we applied a PK model based on data from previous trials that investigated liraglutide doses of 1.8 and 3.0 mg in subjects with overweight or obesity, with or without T2DM.…”

“…19 For the analysis of exenatide ER, which was compared with semaglutide in the SUSTAIN 3 phase 3 trial, 11 we applied a clinical pharmacology population PK model, using data from previous trials with single-dose administration of 2.5, 5, 7 and 10 mg of exenatide ER or weekly doses of 0.8 and 2.0 mg in subjects with T2DM. 20 For the analysis of semaglutide, we applied the SUSTAIN population PK model, which used data from five phase 3 trials, SUSTAIN 1, 2, 3, 6 and SUSTAIN-Japan, which investigated weekly semaglutide doses of 0.5 and 1.0 mg in subjects with T2DM. 21…”

Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant

“…Their pharmacokinetic properties are different, especially in the absorption phase whereby the absorption rate of exenatide BID follows zero‐order kinetics for immediate release of exendin‐4 from the preparation . On the other hand, exenatide QW exhibits first‐order rate in the absorption process indicating a rapid initial release …”