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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

Authors

  • Dr Petra M. Jauslin PhD,

    Corresponding author
    1. Department of Translational Research Sciences, Modeling and Simulation Group, F. Hoffmann-La Roche Inc, Basel, Switzerland
    2. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, University of Uppsala, Sweden
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  • Prof Mats O. Karlsson PhD,

    1. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, University of Uppsala, Sweden
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  • Dr Nicolas Frey PharmD

    1. Department of Translational Research Sciences, Modeling and Simulation Group, F. Hoffmann-La Roche Inc, Basel, Switzerland
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Address for correspondence: Petra M. Jauslin, F. Hoffmann-La Roche Inc, Pharma Research and Early Development, Translational Research Sciences, Building 670 / Room 321, Postfach, CH-4070 Basel, Switzerland; e-mail: petra.jauslin-stetina@roche.com.

Abstract

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.

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