Improvement of the intravenous glucose tolerance test using optimal experimental design.
Hanna E Silber, Joakim Nyberg, Andrew Hooker, Mats O Karlsson
Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden
Background: Intravenous glucose provocations are very informative for studying the glucose-insulin system. The standard IVGTT design contains approximately 30 blood samples of glucose, insulin and labeled glucose during 4 hours following an intravenous bolus dose of glucose. In the insulin modified IVGTT, a 5-minute insulin infusion is given at 20 minutes. Optimal experimental design can be used to increase the efficiency of clinical trials by optimizing the sampling schedule or other design parameters, e.g. dose. When optimal experimental design is used together with population techniques for data analysis we expect the over all trial design to be improved and more efficient with respect to precision of parameter estimates. The objective of this study was to evaluate the possibilities of an improved study design of the insulin modified IVGTT in type 2 diabetic patients.
Methods: A previously developed model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients was implemented in the optimal design software PopED 2.0 [1,2]. In order to decrease run times the number of samples was reduced from 30 to 10. The following aspects of the study design of the insulin modified IVGTT were evaluated; (1) glucose dose, (2) insulin infusion, (3) combination of (1) and (2), (4) sampling times, (5) exclusion of labeled glucose. Constraints were incorporated to avoid prolonged hyper- and/or hypoglycemia. Efficiency was calculated as a measure of the improvement with an optimal design compared to the basic design. The efficiency also corresponds to the reduction in number of subjects that need to be included when an optimal design is used.
Results: The results show that the design of the insulin modified IVGTT can be substantially improved by the use of an optimized design compared to the standard design. The predicted uncertainty of parameter estimates was low in all tested cases, despite the reduction in the number of samples/subject. As an example, the efficiency of the IVGTT could be increased by 304% by a 5-fold increase of the insulin dose, corresponding to a possibility to reduce the number of subjects included in a study to 1/3.
Conclusions: We conclude that substantial improvement can be made to the design of the insulin modified IVGTT. Also when the number of samples is reduced parameters are predicted to be estimated with a high certainty. This illustrates how complex provocation experiments can be improved by sequential modeling and optimal design.
 Silber H E, Jauslin P M, Frey N, Gieschke R, Simonsson U S H, and Karlsson M O. An integrated model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocations. J Clin Pharmacol 2007; 47: 1159-71.
 PopED, version 2.07 (2008) http://poped.sf.net/.