Petra Jauslin (1), Michel Dubar (2), Bernard Sebastien (2), Christian Laveille (1), Per Olsson Gisleskog (1)
(1) SGS Exprimo NV, Mechelen, Belgium, (2) Sanofi-Aventis R&D, Chilly Mazarin, France
Objectives: To develop mechanistic meal test models for lixisenatide, a short-acting prandial GLP-1 receptor agonist [1], and liraglutide, a long-acting one, in order to compare their mechanisms of action and the relative contributions of their respective effect sites to their overall post-prandial glycaemic control.
Methods: Glucose, insulin and glucagon data during meal tests from 143 patients were analysed. The previously published integrated glucose-insulin (IGI) [2] model, developed in NONMEM [3], was extended with a glucagon component. A K-PD [4, 5] analysis of the test drug’s effects on selected parameters (insulin secretion, gastric emptying, hepatic glucose output, glucagon production and insulin sensitivity) was performed. Sites of drug action were added one at a time. The best effect site was selected and all other sites were tested again until no further improvement of fit could be obtained by adding further effect sites.
Results: The IGI+glucagon (IGIG) model was able to adequately describe glucagon profiles in type 2 diabetic patients, capturing its most important interactions with the glucose-insulin system (glucose and insulin effects on glucagon production, glucagon effect on endogenous glucose production and meal effect on glucagon production). The drug-effect model structures for lixisenatide and liraglutide were similar: identified mechanisms of action included suppression of glucagon production and increase of insulin secretion, gastric emptying time and insulin sensitivity. Lixisenatide data were described by a combination of constant and dynamic effects: effects on gastric emptying, glucagon and, in part, insulin secretion were time-dependent. Liraglutide, owing to its longer half-life, exhibited stable drug effects over the test period. Simulations show that the increase of insulin secretion is the most important factor for lowering plasma glucose by liraglutide. For lixisenatide, the gastric emptying effect is most influential during the meal test. The glucagon-mediated effect on post-prandial glycaemic control was not substantial despite both compounds having a significant effect on glucagon production.
Conclusions: The same effect sites were identified for lixisenatide and liraglutide in the meal test situation. However, the relative importance of each effect site differed. Lixisenatide exhibited a profound effect on post-prandial glycaemia, mainly mediated by delaying gastric emptying, as reported for prandial GLP1 agonists.
References:
[1] Bolli GB, Owens DR. Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus. Diabetes Obes Metab. 2013 [Epub ahead of print].
[2] Silber HE, Jauslin PM, Frey N, Karlsson MO. An integrated model for the glucose-insulin system. Basic Clin Pharmacol Toxicol. 2010; 106(3):189-94.
[3] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[4] Jauslin PM, Karlsson MO, Frey N. Identification of the mechanism of action of a glucokinase activator from oral glucose tolerance test data in type 2 diabetic patients based on an integrated glucose-insulin model. J Clin Pharmacol. 2012; 52(12):1861-71.
[5] Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL, Girard P. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007; 34(1): 57-85.
This study was funded by Sanofi.
Reference: PAGE 23 () Abstr 3042 [www.page-meeting.org/?abstract=3042]
Poster: Drug/Disease modeling - Endocrine