TY - JOUR T1 - Mechanism-based pharmacokinetic/pharmacodynamic modeling of the glucagon-like peptide-1 receptor agonist exenatide to characterize its anti-obesity effects in diet-induced obese mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.242651 SP - jpet.117.242651 AU - Shinji Iwasaki AU - Teruki Hamada AU - Ikumi Chisaki AU - Tomohiro Andou AU - Noriyasu Sano AU - Atsutoshi Furuta AU - Nobuyuki Amano Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/07/11/jpet.117.242651.abstract N2 - Glucagon-like peptide-1 (GLP-1) analogs lower body weight in humans in addition to their potent anti-diabetic effects. 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 anti-obesity 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 anti-obesity 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, which 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 utilized for anti-obesity research and development of GLP-1 analogs, GLP-1 secretagogs, GLP-1 degradation inhibitors, and combinations thereof by allowing the estimation of appropriate pharmacokinetic profiles and dosing regimens. ER -