2012 - Venice - Italy

PAGE 2012: Endocrine
Rikke Meldgaard Røge

Integrated model of glucose homeostasis including the effect of exogenous insulin

Rikke M Røge, Søren Klim, Mats O Karlsson, Niels R Kristensen,Steen H Ingwersen,Maria C Kjellsson

Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark,Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

Objectives: Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of non-diabetic subjects and thereby generate normal or near-normal blood glucose levels. In order to regulate the blood glucose in insulin-treated type 2 diabetes mellitus (T2DM) patients, it is important to predict the effect of exogenous insulin on blood glucose. Thus the aim of the study was to develop a model for predicting the 24 hour glucose profiles for T2DM patients and its relation to exogenous insulin administration.

Methods: Data from two trials were included in the analysis. In the first trial two meal tolerance tests (MTT) were performed in 13 T2DM patients. In both MTTs insulin were administered at breakfast and dinner. The insulin was given in the form of biphasic human insulin in one MTT and in the form of biphasic insulin aspart in the other. In the second trial two MTTs were performed in 16 T2DM patients. Biphasic insulin aspart was given immediately before breakfast, lunch, and dinner, but the insulin mixture administered at dinner differed in the two MTTs.
A semi-mechanistic, integrated glucose-insulin (IGI) model has previously been developed to describe MTTs for T2DM patients. The IGI model consists of glucose and endogenous insulin compartments and control mechanisms in the form of effect compartments [1]. The model was extended to allow incorporation of exogenous insulin and its effects on blood glucose. A previously published pharmacokinetic model for insulin aspart [2] was integrated in the IGI model assuming that the effect of insulin aspart was the same as endogenous insulin. The data was analysed using NONMEM7.

Results: The IGI model was extended to include the effect of exogenous insulin. The volume of distribution and clearance of exogenous insulin was initially fixed to the parameters previously obtained for endogenous insulin [1]. However, re-estimating the volume of distribution gave a significant drop in the objective function value. A significant drop in the objective function value was also achieved by including a delayed inhibitory function of glucose concentration on glucose production. 

Conclusions: The IGI model was successfully extended with a component for exogenous insulin. The extended IGI model was able to describe the 24 hour glucose profiles of T2DM patients treated with exogenous insulin. This makes the model a useful tool for clinical trial simulation and for predicting effects of different insulin mixtures.

References:
[1] P.M. Jauslin, N. Frey, and M.O. Karlsson. Modeling of 24-hour glucose and insulin profiles of patients with type 2 diabetes. The Journal of Clinical Pharmacology, 51:153-164, 2011.
[2] W. Clausen, A. De Gaetano, and A. V  lund. Within-patient variation of the pharmacokinetics of subcutaneously injected biphasic insulin aspart as assessed by compartmental modelling. Diabetologia, 49:2030-2038, 2006.




Reference: PAGE 21 (2012) Abstr 2542 [www.page-meeting.org/?abstract=2542]
Poster: Endocrine
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