Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans

Abstract

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 ⅐ min ؊1 ⅐ kg ؊1 ; humans, 1.48 ml ⅐ min ؊1 ⅐ 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.

Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus

“…In the present study, exendin-4 did not modulate gene expression and secretion of FABP4 in 3T3-L1 adipocytes ( Fig. 2B, D, F ), though doses of exendin-4 were well above the reported dissociation constant ( K d ) value of the GLP-1 receptor ( 41,42 ). Hence, the present regulatory factors of lipolysis, sympathetic tone and infl ammatory cytokines, are potentially modulated by pharmacological inhibition of DPP-4.…”

Learning curve of vessel cannulation in rats using cumulative sum analysis

“…Vessel cannulation in animals has been the cornerstone for performing PK experiments and is the standard practice in drug discovery as it has been shown to provide accurate and reliable results [12][13][14][15][16][17]. PK experiments involve administering the drug compound and taking blood samples in order to assess the biological effect.…”

“…The cannulation of these vessels was used in an animal model developed in-house in order to evaluate the pharmacokinetic properties (PK) of peptides developed as part of a drug discovery anti-obesity program. The use of animals for such PK experiments is standard practice and provides accurate and reliable results [12][13][14][15][16][17]. Optimal and timely vessel cannulation is important for this protocol; time is a critical component when performing PK experiments as there are limitations to time animals can remain under anaesthesia.…”

Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model

“…Over the last two decades, the use of PK modelling techniques to aid investigating the drug actions has become standard practice [8,9]. Rodents, and in particular rats, are extensively used as experimental models for PK studies helping to optimise and select drugs prior to human trials [8,[10][11][12][13][14][15].…”