Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans

Abstract

A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for exendin-4 to account for receptor-mediated endocytosis via glucagon-like peptide 1 receptor (GLP-1R) as the primary mechanism for its nonlinear disposition. Time profiles of exendin-4 concentrations after intravenous, subcutaneous, and continuous intravenous infusion doses in rats, intravenous and subcutaneous doses in monkeys, and intravenous infusion and subcutaneous doses in humans 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, nonspecific 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 the central compartment (CL(c)) (rats, 3.62 ml/min; monkeys, 2.39 ml · min(-1) · kg(-1); humans, 1.48 ml · min(-1) · kg(-1)) 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), whereas the value in monkeys (0.12 pM) was much lower than that in humans (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 after 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.

Fig. 1.

Scheme of the target-mediated PK/PD model for exendin-4. Symbols are defined in the text and tables.

Fig. 2.

Exendin-4 concentration versus time profiles after single intravenous (iv) and s.c. doses of 0.5, 5, and 50 nmol and continuous iv infusion at doses of 0.5, 5, and 50 nmol/h in rats. Symbols are mean drug concentrations with error bars representing S.E. (n = 4–7), and solid lines are fitted profiles.

Fig. 3.

Exendin-4 concentration versus time profiles after single intravenous (iv) and s.c. doses of 1, 3, and 10 μg/kg in monkeys. Symbols are mean drug concentrations with error bars representing S.E. (n = 3), and solid lines are fitted profiles.

Fig. 4.

Exendin-4 concentration versus time profiles after single subcutaneous doses (top, study A; middle, study B) and iv infusion (bottom, study C) in humans. Symbols are mean drug concentrations with error bars representing S.E (n = 7–8), and solid lines are fitted profiles.

Fig. 5.

Time profiles of glucose (left) and insulin (right) concentrations in rats during saline (A) or drug [3 (B), 30 (C), 300 (D), and 3000 (E) pmol · kg⁻¹ · min⁻¹] infusions with glucose bolus challenge at 30 min. Symbols are mean concentrations with error bars representing S.E. (n = 4–8), and solid lines are fitted profiles.

Fig. 6.

Simulated exendin-4 concentration profiles at various infusion rates in the PD study (top) and the relationship between S_Glu estimates and exendin-4 concentration at 30 min after the start of drug infusions (bottom).

Fig. 7.

The relationship of estimated values of k_a versus dose (A) and selected PK parameters [CL_c (B), V_c (C), and k_off (D)] versus body weight in rats, monkeys, and humans.

Fig. 8.

Simulated insulin responses (picomoles) after glucose challenge with various exendin-4 infusion rates according to the PK/PD model.