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 (ka) decreased with increasing doses in all three species. The clearance from the central compartment (CLc) (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 (CLc, Vc, and koff) correlated allometrically with body weight. The equilibrium dissociation constant (KD) 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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM57980].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- GLP-1
- glucagon-like peptide 1
- GLP-1R
- GLP-1 receptor
- PK
- pharmacokinetics
- TMDD
- target-mediated drug disposition
- PD
- pharmacodynamics
- SD
- Sprague-Dawley
- NCA
- noncompartmental analysis
- GFR
- glomerular filtration rate
- GK
- Goto-Kakizaki
- RC
- receptor complex
- AIC
- Akaike's information criterion.
- Received August 10, 2011.
- Accepted February 15, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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