title: 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.
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.
authors.affiliation: F. Hoffmann-La Roche Inc, Pharma Research and Early Development, Translational Research Sciences, Building 670 / Room 321, Postfach, CH-4070 Basel, Switzerland. petra.jauslin-stetina@roche.com
authors.forename: Petra M
authors.initials: PM
authors.lastname: Jauslin
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frey
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D007328:Insulin; D005941:Glucokinase; D005947:Glucose