Evaluation of immediate release exenatide effects on gastric motility and intestinal glucose absorption using a systems pharmacology model
Veronika Voronova1, Kirill Zhudenkov1, Robert C. Penland2a, David W. Boulton2b, Gabriel Helmlinger2a, Kirill Peskov1
1M&S Decisions, Moscow, Russia; 2Quantitative Clinical Pharmacology, AstraZeneca; 2aWaltham, MA, USA; 2bGaithersburg, MD, USA.
Objectives: Glucagon-like peptide (GLP)-1 and other GLP-1 receptor agonists such as exenatide have been shown to decrease gastric motility [1,2]. This class effect may slow exogenous glucose absorption rate from the gastro-intestinal tract (exGluRa) and consequently modulate postprandial plasma glucose dynamics. The objective of the current modeling study was to evaluate immediate release (IR) exenatide effects on the gastric emptying rate (GER) and exGluRa after administration of liquid or a mixed carbohydrate-containing meal.
Methods: The model is described as a system of ordinary differential equations and can be divided into: (1) a food sub-model, to describe food retention in the stomach during placebo or GLP-1 infusion; (2) an acetaminophen absorption rate sub-model, to capture the effects of exenatide on GER; and (3) a glucose sub-model, to describe glucose transition from the stomach to the intestine and subsequent absorption into the systemic circulation. A published popPK model was used to reproduce experimental plasma exenatide kinetics . Plasma GLP-1 concentrations in the model were set according to experimental conditions. Modeling was performed in Matlab using IQM Tools (http://www.intiquan.com/).
Results: Both GLP-1 and exenatide effects on gastric motility were adequately reproduced by the model; so were rates of exGluRa after administration of different food types. The model was then used to predict exGluRa in response to twice-daily 5- or 10-ug exenatide subcutaneous injections and three time daily liquid or mixed-food intake
Exenatide was shown to cause a split in the exGluRa peak, with a pronounced reduction in the maximal absorption rate of 40-60% after liquid food ingestion. In contrast, after intake of a mixed meal, exenatide treatment caused a significant delay of glucose absorption and delayed Tmax by 2.7 hours, yet, had a mild effect on the peak magnitude (5% reduction). Treatment effect was less pronounced with lunch meals, vs. morning and evening meals, the latter being combined with drug administration (hence higher target occupancy).
Conclusion: A mechanistic systems model describing GLP-1 and exenatide effects on gastric motility was developed. It was shown that inhibition of gastric emptying does affect intestinal glucose absorption, a mechanism whereby GLP-1 analogues may modulate postprandial plasma glucose dynamics. The proposed model also supports the recommended exenatide administration regimen and the model may be used for the optimization of other GLP-1 agonist-based therapies.
 Meier JJ et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003 Jun;88(6):2719-25.
 Kolterman OG et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005 Jan 15;62(2):173-81.
 FDA Clinical Pharmacology Review for BYDUREON (Exanatide LAR). July 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000ClinPharmR.pdf