Pharmacokinetics,in vitroandin vivocorrelation, and efficacy of exenatide microspheres in diabetic rats

Abstract

Modeling and simulation are aimed at achieving information about the behaviors of the drugs without the actual measurements and determination. The purpose of this study was to characterize the in vivo behavior of exenatide microspheres using model-based methods. Exenatide is a glucagon-like peptide-1 agonist medication, belonging to the group of incretin mimetics, approved for the treatment of diabetes mellitus type 2. An oil-in-water solvent evaporation method was used to prepare the exenatide microspheres and their physicochemical features were investigated. After subcutaneous injection of exenatide microspheres to streptozotocin-induced diabetic rats, the exenatide concentrations increased and kept increasing and the blood glucose decreased in all diabetic rats. The in vivo release behavior of exenatide from microspheres was described by a transit compartment model. Based on the transit compartment model, the simulation method was proposed for the description of in vivo release. The in vitro and in vivo correlation (IVIVC) was established by the model-based simulation (R(2) = 0.903) and deconvolution (R(2) = 0.922) methods successfully. Using a transit compartment model to characterize the in vivo exenatide release from microspheres is an acceptable approach, and the IVIVC can be estimated reliably with the model-based simulation method.

Effect of Stabilizers on Encapsulation Efficiency and Release Behavior of Exenatide-Loaded PLGA Microsphere Prepared by the W/O/W Solvent Evaporation Method

“…Unlike quantitative analysis of un-degraded exenatide using RP-HPLC, extracted exenatide from lyophilized microspheres was analyzed by circular dichroism (CD) spectroscopy to examine the changes in secondary structure in aqueous solution compared to unprocessed exenatide [12,18]. The CD spectra of exenatide had two specific minima at 209 and 224 nm wavelength, which indicated the presence of α-helix (Figure 8a) [25]. There was no difference between the extracted exenatide from ELPM6 and the unprocessed one, which means that the secondary structure of exenatide in ELPM6 microspheres can be maintained after the W/O/W-SE and lyophilization processes using a combination of various stabilizers [28,31].…”

“…For example, adverse effects like vomiting may increase with higher rates of exenatide burst release [11]. Many groups are currently attempting to suppress exenatide burst release and the incomplete release of commercial products [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Although many investigations into exenatide formulations and dosages have been performed, there is still a lack of useful information about exenatide stability.…”

In vitro–in vivo correlation for complex non-oral drug products: Where do we stand?

“…sample-and-separate [23,26,27], membrane dialysis [14,22], and flow through [15,16]) have been utilized to determine in vitro drug release characteristics and to develop IVIVCs. Although it is feasible to develop IVIVCs for parenteral microspheres/implants based on a simple sample-and-separate method [17,[23][24][25], there are limitations associated with this method such as poor hydrodynamic conditions, loss of product (e.g. microspheres) during sampling as well as inability to mimic different in vivo drug release conditions.…”

Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

“…However, the deconvolution method has difficulties in determining the correlation between in vitro and in vivo profiles of SR injection, which makes it difficult to interpret its disposition as a conventional Pharmaceutics 2020, 12, 36 3 of 16 one-compartment or two-compartment model. Li et al established an IVIVC model for exenatide through simulation modeling to overcome the shortcomings of the traditional deconvolution method [9]. The simulation model they developed is more predictable than the deconvolution method when using the same in vitro and in vivo data.…”