H. Silber (1), P. Stetina (1), B. McHugh (2), R. Gieschke (2), N. Frey (2), P. Vicini (3), U.S.H. Simonsson (1), M.O. Karlsson (1)
(1) Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Clinical Pharmacology, Modeling and Simulation Group, F. Hoffmann-La Roche, Basel, Switzerland; (3) Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, Washington, USA
Objectives: The aim of this project was to develop a mechanistic model to describe the glucose and insulin regulation following different kinds of glucose provocations, such as an intravenous glucose tolerance test (IVGTT), in healthy volunteers and type II diabetic patients.
Methods: The model was developed based on mechanistic knowledge of the insulin-glucose regulation. Data without drug-effect from four different trials with a total of 72 individuals (30 volunteers and 42 patients) were used. All patients and 24 of the volunteers received a single intravenous dose of glucose (250-330 mg/kg). The glucose was enriched with [6,6-2H2]glucose, on average 10% of the total glucose dose. After 20 minutes the patients and 10 of the volunteers received a 5-minute insulin infusion (patients 0.05 U/kg and volunteers 0.03 U/kg). The remaining 6 volunteers received a single bolus dose of [3-3H]glucose at basal (14 μU/ml) and at elevated (110 μU/ml) insulin levels. Glucose was kept constant at 87.5 mg/dl. Blood samples were drawn pre-dose and until 240 minutes post-dose for the determination of plasma glucose, [6,6-2H2]glucose, [3-3H]glucose and insulin concentrations. These concentrations versus time data were modeled simultaneously by non-linear mixed effect modeling using NONMEM.
Results: The glucose sub-model contained a two-compartment disposition model with endogenous production and insulin dependent and independent elimination. The insulin sub-model contained a two-compartment disposition model with endogenous production and release. Labeled glucose was also described with a two-compartment disposition model with insulin dependent and independent elimination. Feedback loops were incorporated into the model to account for the regulation of glucose production and elimination and for insulin production. Parameters with similar values for volunteers and patients were merged whereas other parameters were estimated separately for the two subpopulations in the model.
Conclusion: The model presented here allows the simultaneous prediction of insulin, glucose and labeled glucose levels without drug effect in volunteers and patients which can be of use in the development of antidiabetic drugs.
Reference: PAGE 13 (2004) Abstr 541 [www.page-meeting.org/?abstract=541]
Poster: poster