Pharmacokinetic dynamic relationships
Population PK/PD analysis of metformin using the signal transduction model
Article first published online: 9 OCT 2012
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 74, Issue 5, pages 815–823, November 2012
How to Cite
Chae, J.-w., Baek, I.-h., Lee, B.-y., Cho, S.-k. and Kwon, K.-i. (2012), Population PK/PD analysis of metformin using the signal transduction model. British Journal of Clinical Pharmacology, 74: 815–823. doi: 10.1111/j.1365-2125.2012.04260.x
- Issue published online: 9 OCT 2012
- Article first published online: 9 OCT 2012
- Accepted manuscript online: 1 MAR 2012 09:00AM EST
- Received; 7 February 2011; Accepted; 24 February 2012; Accepted Article Published Online; 1 March 2012
- antihyperglycaemic effect;
- signal transduction model;
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes.
• The molecular mechanisms of metformin have not been fully identified, but turnover of biomarkers such as glucose and signalling pathways or translocation of glucose transporters are closely related to the glucose-lowering effects of metformin.
• The PK/PD of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus and modelling has been performed using an indirect response model.
WHAT THIS STUDY ADDS
• The purpose of this investigation was to develop a population PK/PD model for metformin using a signal transduction model in healthy humans and predict the PK/PD profile in patients with type 2 diabetes.
• The aim was to compare a previous model (a biophase model) with the signal transduction model, and use a more appropriate model to follow the actions of metformin.
• Additionally, our developed model was appropriate to predict the time course of plasma metformin and fasting plasma glucose (FPG) concentrations in patients with type 2 diabetes.
• To our knowledge, this is the first published population PK/PD analysis using the signal transduction model for metformin.
AIMS To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes.
METHODS Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes.
RESULTS Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h−1 (4.18%), 113 l (56.6%) and 0.41 h−1, respectively. Covariate analyses revealed that creatinine clearance (CLCR) significantly influenced metformin: CL/F= 52.6 × (CLcr/106.5)0.782. The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml−1 (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values.
CONCLUSIONS The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.