title: Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function.
abstract: OBJECTIVE
  Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function.
  
  
  METHODS
  Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit.
  
  
  RESULTS
  Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations.
  
  
  CONCLUSIONS
  The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.
authors.affiliation: School of Medical Sciences, University of New South Wales, Kensington, Sydney, NSW, Australia.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Duong
authors.forename: Shaun S
authors.initials: SS
authors.lastname: Kumar
authors.forename: Carl M
authors.initials: CM
authors.lastname: Kirkpatrick
authors.forename: Louise C
authors.initials: LC
authors.lastname: Greenup
authors.forename: Manit
authors.initials: M
authors.lastname: Arora
authors.forename: Toong C
authors.initials: TC
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Timmins
authors.forename: Garry G
authors.initials: GG
authors.lastname: Graham
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Furlong
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Greenfield
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Williams
authors.forename: Richard O
authors.initials: RO
authors.lastname: Day
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008296:Malaysia; D026901:Membrane Transport Proteins / Q000235:genetics; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D020641:Polymorphism, Single Nucleotide; D051437:Renal Insufficiency / Q000503:physiopathology*; D014018:Tissue Distribution; D044465:White People; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D026901:Membrane Transport Proteins; D008687:Metformin