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

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Wei Gao, William J Jusko

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), wherea...Continue Reading

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Citations

Dec 12, 2012·Pharmaceutical Research·Ting ChenLeonid Kagan
May 24, 2014·Pharmaceutical Research·Leonid KaganDonald E Mager
Apr 2, 2013·Advanced Drug Delivery Reviews·Eric Ezan
Sep 6, 2014·Journal of the American Chemical Society·Lisa M JohnsonSamuel H Gellman
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Aug 2, 2014·The Journal of Surgical Research·Ioannis ChristakisStephen Bloom
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Sep 22, 2016·British Journal of Clinical Pharmacology·Brenda Cirincione, Donald E Mager
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May 5, 2017·Frontiers in Bioengineering and Biotechnology·Magnus TrägårdhPeter Gennemark

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