Pharmacokinetic-Pharmacodynamic Modeling of Metformin for the Treatment of Type II Diabetes Mellitus

Metformin is an antihyperglycemic agent commonly used for the treatment of Type II diabetes mellitus. However, its effects on patients are derived usually from clinical experiments. In this study, a dynamic model of Type II diabetes mellitus with the treatment of metformin is proposed. The Type II diabetic model is a modification of an existing compartmental diabetic model. The dynamic simulation of the metformin effect for a Type II diabetic patient is based on the pharmacokinetic and pharmacodynamic relationship with a human body. The corresponding model parameters are estimated by optimization using clinical data from published reports. Then, the effect of metformin in both intravenous and oral administration on a Type II diabetes mellitus model are compared. The combination treatment of insulin infusion plus oral metformin is shown to be superior than the monotherapy with oral metformin only. These results are consistent with the clinical understanding of the use of metformin. For further work, the model can be analyzed for evaluating the treatment of diabetes mellitus with different pharmacological agents.

[1]  C. Cobelli,et al.  Validation of mathematical models of complex endocrine-metabolic systems. A case study on a model of glucose regulation , 1983, Medical and Biological Engineering and Computing.

[2]  J. H. Burke,et al.  Portal blood flow in cirrhosis of the liver. , 1967, The Journal of clinical investigation.

[3]  B. Ploeger,et al.  Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research. , 2008, Trends in pharmacological sciences.

[4]  R. DeFronzo,et al.  Metformin: A review of its metabolic effects , 1998 .

[5]  D. Skaar,et al.  Metformin, a Promising Oral Antihyperglycemic for the Treatment of Noninsulin‐Dependent Diabetes Mellitus , 1997, Pharmacotherapy.

[6]  M. Ibbini,et al.  A fuzzy logic based closed-loop control system for blood glucose level regulation in diabetics , 2005, Journal of medical engineering & technology.

[7]  C. Bailey,et al.  A Risk-Benefit Assessment of Metformin in Type 2 Diabetes Mellitus , 1999, Drug safety.

[8]  E D Lehmann,et al.  A physiological model of glucose-insulin interaction in type 1 diabetes mellitus. , 1992, Journal of biomedical engineering.

[9]  Development of a physiological model forpatients with type 2 diabetes mellitus , 2010, Proceedings of the 2010 American Control Conference.

[10]  V. Bolie,et al.  Coefficients of normal blood glucose regulation. , 1961, Journal of applied physiology.

[11]  C. Bailey,et al.  Reconsideration of inhibitory effect of metformin on intestinal glucose absorption , 1991, The Journal of pharmacy and pharmacology.

[12]  John Thomas Sorensen,et al.  A physiologic model of glucose metabolism in man and its use to design and assess improved insulin therapies for diabetes , 1985 .

[13]  P. Neuvonen,et al.  Pharmacokinetics of metformin after intravenous and oral administration to man , 1979, European Journal of Clinical Pharmacology.

[14]  K. Kwon,et al.  Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers , 2004, Archives of pharmacal research.

[15]  I. Dicembrini,et al.  A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients. , 2007, Diabetes research and clinical practice.

[16]  K. Johansen Efficacy of metformin in the treatment of NIDDM. Meta-analysis. , 1999, Diabetes care.

[17]  A. Hoffman,et al.  Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[18]  MS Ibbini,et al.  A semiclosed-loop optimal control system for blood glucose level in diabetics , 2004, Journal of medical engineering & technology.

[19]  A. Hoffman,et al.  Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[20]  A Schumitzky,et al.  A program package for simulation and parameter estimation in pharmacokinetic systems. , 1979, Computer programs in biomedicine.