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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2012 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, no 12, 1861-1871 p.Article in journal (Refereed) Published
Abstract [en]

A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model’s ability to identify a drug’s mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug’s pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate’s mechanism of action.

Place, publisher, year, edition, pages
2012. Vol. 52, no 12, 1861-1871 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97189DOI: 10.1177/0091270011422231ISI: 000310681200008OAI: oai:DiVA.org:uu-97189DiVA: diva2:172013
Available from: 2008-04-28 Created: 2008-04-28 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mechanism-Based Modeling of the Glucose-Insulin Regulation during Clinical Provocation Experiments
Open this publication in new window or tab >>Mechanism-Based Modeling of the Glucose-Insulin Regulation during Clinical Provocation Experiments
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is a complex chronic metabolic disorder characterized by hyperglycemia associated with a relative deficiency of insulin secretion and a reduced response of target tissues to insulin. Considerable efforts have been put into the development of models describing the glucose-insulin system. The best known is Bergman’s “minimal” model for glucose, which is estimating glucose concentrations using fixed insulin concentrations as input. However, due to the involved feedback mechanisms, simultaneous modeling of both entities would be advantageous. This is particularly relevant if the model is intended to be used as a predictive tool. The mechanism-based glucose-insulin model presented in this thesis is able to simultaneously describe glucose and insulin profiles following a wide variety of clinical provocation experiments, such as intravenous and oral glucose tolerance tests, clamp studies and sequential meal tests over 24 hours. It consists of sub-models for glucose, labeled glucose and insulin kinetics. It also incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM.

Even if this model is a crude representation of a complex physiological system, its ability to represent the main processes of this system was established by identifying: 1) the difference in insulin secretion and insulin sensitivity between healthy volunteers and type 2 diabetics, 2) the action of incretin hormones after oral administration of glucose, 3) the circadian variation of insulin secretion and 4) the correct mechanism of action of a glucokinase activator, a new oral antidiabetic compound acting on both the pancreas and the liver.

These promising results represent a proof of concept of a mechanistic drug-disease model that could play an important role in the clinical development of anti-diabetic drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 73
Keyword
Pharmacokinetics/Pharmacotherapy, Glucose homeostasis, Type 2 diabetes, IVGTT, OGTT, Meal test, Circadian variation, Mechanism-based, NONMEM, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-8719 (URN)978-91-554-7195-8 (ISBN)
Public defence
2008-05-23, B21, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2008-04-28 Created: 2008-04-28 Last updated: 2011-03-21Bibliographically approved

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Karlsson, Mats O

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