Abstract

A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for exendin-4 to account for receptor-mediated endocytosis via GLP-1 receptor (GLP-1R) as the primary mechanism for its nonlinear disposition. Time profiles of exendin-4 concentrations following intravenous (iv), subcutaneous (sc) and continuous iv infusion doses in rats, iv and sc doses in monkeys, and iv infusion and sc doses in man were examined. Mean data for glucose and insulin after glucose challenges during exendin-4 treatment in healthy rats were analyzed. The PK model components included receptor binding, subsequent internalization and degradation, non-specific tissue distribution, and linear first-order elimination from plasma. The absorption rate constant (k_a) decreased with increasing doses in all three species. The clearance from central compartment (CL_c) (rats: 3.62 ml/min, monkeys: 2.39 ml/min/kg, man: 1.48 ml/min/kg) was similar to reported renal clearances. Selected PK parameters (CL_c, V_c and k_off) correlated allometrically with body weight. The equilibrium dissociation constant (K_D) was within the reported range in rats (0.74 nM), while the value in monkeys (0.12 pM) was much lower than in man (1.38 nM). The effects of exendin-4 on the glucose-insulin system were described by a feedback model with a biphasic effect equation driven by free exendin-4 concentrations. Our generalized nonlinear PK/PD model for exendin-4 taking into account of drug binding to GLP-1R well described PK profiles following various routes of administration over a large range of doses in three species along with PD responses in healthy rats. The present model closely reflects underlying mechanisms of disposition and dynamics of exendin-4.