Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes . Metformin is used as monotherapy, as an adjunct to diet for managing type 2 diabetes mellitus in patients whose hyperglycaemia cannot be controlled by diet alone . Metformin may also be used in combination with other antidiabetic agents in patients with type 2 diabetes who do not achieve adequate glycaemic control with a sulfonylurea agent alone . The glucose lowering effect of metformin is primarily the result of reduced hepatic glucose output through inhibition of gluconeogenesis and glycogenolysis . The glucose lowering effect of metformin vs. the plasma concentration curve shows a counter clock-wise hysteresis loop .
Biophase models are most appropriate when delay in drug action occurs from the distribution site to the site of action . However, this modelling approach is often applied inappropriately when the most relevant underlying process that causes the delay is not drug distribution. Other reasons, such as glucose turnover, signalling pathways or translocation of glucose transporters, may be more relevant to the action of antidiabetic drugs . Moreover, the turnover and homeostasis of glucose and insulin is not accounted for by biophase models. Signal transduction models describe a drug mechanism that immediately alters the production or loss of endogenous substances, and, therefore, are the most useful when turnover (glucose concentration) can be measured directly .
The pharmacokinetics (PK) and pharmacodynamics (PD) of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus [5, 9–11], and modelling has been performed using an indirect response model . However, the indirect response model is insufficient to explain the PK/PD relationship and describe the visual inspection of metformin. No reported study clearly describes the glucose lowering effect and the plasma concentrations of metformin in healthy humans using the NONMEM program and the signal transduction model method.
The objectives of this study were to examine the relationship between the plasma concentration of metformin and its antihyperglycaemic effect in healthy humans following administration of a single 500 mg metformin tablet. A Monte Carlo simulation was performed using the ADAPT 5 program (Biomedical Simulation Resource, Los Angeles, CA, USA) to predict plasma glucose concentrations in patients with diabetes. The model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to that of previous studies [12, 13] in patients with diabetes. Thus, the proposed model was able to predict the antihyperglycaemic effect.