ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 39 citations in OpenAlex.
- Population Pharmacokinetic and Pharmacodynamic Modeling of LY2510924 in Patients With Advanced Cancer.CPT: pharmacometrics & systems pharmacology · 2017Trial
- Assessment of glycemic response to an oral glucokinase activator in a proof of concept study: application of a semi-mechanistic, integrated glucose-insulin-glucagon model.Journal of pharmacokinetics and pharmacodynamics · 2013Trial
- Systemic Pharmacokinetic Principles of Therapeutic Peptides.Clinical pharmacokinetics · 2026Article
- Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.British journal of pharmacology · 2020Article
- Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists.Molecular metabolism · 2020Article
- Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon.Scientific reports · 2019Article
- Article
- Toward Better Understanding of Insulin Therapy by Translation of a PK-PD Model to Visualize Insulin and Glucose Action Profiles.Journal of clinical pharmacology · 2019Article
- Model-Based Evaluation of Exenatide Effects on the QT Interval in Healthy Subjects Following Continuous IV Infusion.Journal of clinical pharmacology · 2017Article
- Population pharmacokinetics of exenatide.British journal of clinical pharmacology · 2017Article
- Input Estimation for Extended-Release Formulations Exemplified with Exenatide.Frontiers in bioengineering and biotechnology · 2017Article
- Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones.ACS chemical biology · 2016Article
- Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus.Journal of lipid research · 2015Article
- A Tutorial on Target-Mediated Drug Disposition (TMDD) Models.CPT: pharmacometrics & systems pharmacology · 2015Article
- Article
- Interspecies pharmacokinetic modeling of subcutaneous absorption of rituximab in mice and rats.Pharmaceutical research · 2014Article
- A potent α/β-peptide analogue of GLP-1 with prolonged action in vivo.Journal of the American Chemical Society · 2014Article
- Exenatide twice daily: a review of its use in the management of patients with type 2 diabetes mellitus.Drugs · 2014Review
- Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research.Frontiers in pharmacology · 2014Review
- Interspecies modeling and prediction of human exenatide pharmacokinetics.Pharmaceutical research · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.