title: Population PK/PD analysis of metformin using the signal transduction model.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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 (CL(CR) ) significantly influenced metformin: CL/F= 52.6 × (CL(cr) /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.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Korea.
authors.forename: Jung-woo
authors.initials: JW
authors.lastname: Chae
authors.forename: In-hwan
authors.initials: IH
authors.lastname: Baek
authors.forename: Byung-yo
authors.initials: BY
authors.lastname: Lee
authors.forename: Seong-kwon
authors.initials: SK
authors.lastname: Cho
authors.forename: Kwang-il
authors.initials: KI
authors.lastname: Kwon
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D002853:Chromatography, Liquid; D003404:Creatinine / Q000097:blood / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin; D003404:Creatinine