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.

Pharmacodynamic effects of the oral glucokinase activator AZD6370 after single doses in healthy volunteers assessed with euglycaemic clamp

“…Nonetheless, our data are in line with those of Jauslin et al [28], who incorporated the results of an oral glucose tolerance test into a glucose-insulin model. However, with approximately threefold higher doses of AZD6370 (150 mg) and short-acting insulin (12 U), the effects on both GIR and peripheral S-insulin levels were comparable between the treatments.…”

Study Design Selection in Early Clinical Anti‐Hyperglycemic Drug Development: A Simulation Study of Glucose Tolerance Tests

“…The main design aspects of each of the standard glucose provocations are listed in Supplementary Table . The designs were inspired by published studies of glucose experiments . The MTT‐24 design is the only study in which patients received repeated glucose: three meals (8 am , 2 pm , and 8 pm ) and three snacks (11 am , 5 pm , and 11 pm ) and the NO design is the only study design in which no glucose is given.…”

Implications for Drug Characterization in Glucose Tolerance Tests Without Insulin: Simulation Study of Power and Predictions Using Model‐Based Analysis

“…(listed in Table ). The model, developed by Jauslin et al ., was chosen because it is a closed‐loop system, enabling integrated simulations of glucose and insulin, and it has shown good estimation and prediction performance as well as the ability to characterize drug effects …”

“…These glucose challenges are typically performed after a single dose of study drug/placebo or a short induction phase (e.g., 7 days). After a period of fasting, blood sampling is started with fasting blood sample(s), followed by glucose administration, and then blood samples are taken periodically (for example, every 30 minutes for 3–8 hours) . These samples are analyzed with regard to glucose and insulin to generate dynamic profiles in the absence and presence of the study compound.…”