Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide to Characterize Its Antiobesity Effects in Diet-Induced Obese Mice.

Abstract

In addition to their potent antidiabetic effects, glucagon-like peptide-1 (GLP-1) analogs lower body weight in humans. Hence, agonistic targeting of the GLP-1 receptor could be a valid approach to target obesity. However, quantitative analyses of the pharmacokinetic/pharmacodynamic (PK/PD) relationship between GLP-1 analogs and their antiobesity effect have not been reported in either animals or humans. Therefore, the present study was performed to establish a mechanism-based PK/PD model of GLP-1 receptor agonists using the GLP-1 analog exenatide for the development of promising new antiobesity drugs. Exenatide was administered to high-fat diet-induced obese C57BL/6J mice via subcutaneous bolus and continuous infusion. Food intake and body-weight reductions were observed and depended on the plasma concentrations of exenatide. The homeostatic feedback model, in which food intake is assumed to be regulated by appetite control signals, described the relationship among the plasma concentration-time profile of exenatide, food intake, and body weight. The estimated IC50 of exenatide against food intake was 2.05 pM, which is similar to the reported KD value of exenatide in rat brain and the estimated EC50 value for augmentation of insulin secretion in humans. The PK/PD model simulation indicated that subcutaneous infusion would show a stronger effect on body-weight reduction than bolus dosing would. This novel, quantitative PK/PD model could be used for antiobesity research and development of GLP-1 analogs, GLP-1 secretagogues, GLP-1 degradation inhibitors, and combinations thereof by allowing the estimation of appropriate pharmacokinetic profiles and dosing regimens.