Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

Abstract

A hybrid pharmacokinetic/pharmacodynamic (PK/PD) model with extended-release (ER) process and target mediated drug disposition (TMDD) was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R)-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM) were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol.

Input Estimation for Extended-Release Formulations Exemplified with Exenatide

“…This result holds for intravenous (IV) administration, either bolus or continuous, as well as for subcutaneous (SC) administration. Since the model in Chen et al (2013) shares the model structure of the PK after absorption with Li et al (2015), it follows that this too is identifiable for IV administration. To summarize, any of these models could have been used in the subsequent analysis.…”

“…The analysis showed that the PK models in Li et al (2015) and Gao and Jusko (2012) are structurally identifiable. This result holds for intravenous (IV) administration, either bolus or continuous, as well as for subcutaneous (SC) administration.…”

“…In addition to the model presented in Gao and Jusko (2012), similar models have been developed by Li et al (2015) and Chen et al (2013). These models differ from that of Gao and Jusko in that the total receptor concentration is described by a turnover model, instead of a fixed amount.…”

“…The reason for choosing Bydureon as an example is that it is a drug that is already on the market, and data (Fineman et al, 2011; Li et al, 2015) as well as PK models (Gao and Jusko, 2012) are available in the literature. The complicated absorption profile of exenatide (Figure 2) cannot be easily captured by a simple parametric model.…”

“…The complicated absorption profile of exenatide (Figure 2) cannot be easily captured by a simple parametric model. A compartmental model of the release and absorption processes has been proposed (Li et al, 2015), where the ER process is modeled by a cascade of transition compartments, and the initial amount of several compartments is non-zero. However, this model was designed to fit data from multiple-dosing experiments, where the multiple absorption peaks are not as noticeable.…”