Identification of the Mechanism of Action of a Glucokinase Activator from OGTT Data in Type 2 Diabetics Using an Integrated Glucose-Insulin Model
P. M. Jauslin (1,2), M. O. Karlsson (1), N. Frey (2)
(1) Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, University of Uppsala, Sweden; (2) Department of Biomathematics, Modeling and Simulation Group, F. Hoffmann-La Roche Inc., Basel, Switzerland
Objectives: To demonstrate the ability of a previously developed integrated glucose-insulin model to identify the correct dual mechanism of action of a glucokinase activator (GKA) and to estimate the drug's antidiabetic effects based on oral glucose tolerance test (OGTT) data in type 2 diabetics.
Methods: The data were obtained from a three-period cross-over study in type 2 diabetic patients. Each patient received placebo and 2 different doses (25 mg and 100 mg) of the study drug. The drug was administered in fasting state. Two hours later, an OGTT was performed. A kinetic-pharmacodynamic (K-PD) approach was chosen to describe the pharmacodynamic effect of the study drug in a dose-response-time model. Based on the integrated glucose-insulin model for OGTTs in type 2 diabetics developed by Jauslin et al [1], model parameters that were likely to be affected by the action of a antidiabetic drugs were identified: insulin secretion, glucose production, the insulin effect on glucose elimination and insulin-independent glucose elimination. Drug effects at the different sites of action were first tested one by one and then in combination.
Results: The integrated glucose-insulin model was able to identify the correct dual mechanism of action of a GKA: targeting the drug effect on insulin secretion and glucose output resulted in a significantly better model fit than any other combination of effect sites. The model was also able to quantify the effect of both GKA doses on the patients' glucose and insulin concentration-time profiles.
Conclusions: These promising results prove the ability of this mechanism-based glucose-insulin model to identify a compound's mechanism of action and to describe its effects on glucose and insulin time courses. However, the approach requires further validation by application to other compounds with different mechanisms of action. The model might find its main application in the earlier stages of drug development, particularly by gaining information on drug exposure-response relationships from glucose challenges.
References:
[1] Jauslin P, Silber HE, Frey N, Gieschke R, Simonsson US, Jorga K, Karlsson MO. An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics. J Clin Pharmacol. 2007;47:1244-55.