Population Pharmacokinetics of Metformin in Mexican Patients with Type 2 Diabetes Mellitus

The aim of this study was to develop a Population Pharmacokinetic Model (PPM) for Metformin and to determine the influence of physiologic covariates on its pharmacokinetic variability in patients with Type 2 Diabetes Mellitus (T2DM). Ninety-nine patients with T2DM were included in the study. The clinical and pharmacokinetic data of 81 patients were used to build the population model and validated in others 18 patients. All patients received Metformin at a dose of 500-850 mg every 8 h. Blood samples were obtained at 2, 4, 6 or 8 h after drug administration, levels of drug were assayed by high performance liquid chromatography. The PPM was built using a nonlinear mixed effect program. The PPM was fitted to an open one compartment model, Ka = 2.22 h(-1) (CV61.5%), CL/F = 26.4 L h(-1) (CV 50.2%) and V/F = 365 L (CV 34.1%). Creatinine clearance (CLcr) and Lean Body Weight (LBW) correlated significantly with CL/F and V/F, respectively. The inclusion of these covariates in the basic model improved significantly the prediction performance as evaluated by the log-likelihood function. The final model was: CL/F = 16.6xexp (0.00546xCLcr), V/F = 209xexp (0.0112xLBW), with CV of 47 and 31.2%, respectively. In the PPM of metformin in Mexican patients with T2DM here described, the covariates, LBW and CLcr had a significant influence on interindividual variability of V/F and CL/F. Model evaluation suggested that the PPM is robust and its parameters were estimated with good precision. The model may be useful for clinician to design a rational initial dosage regimen in this patient population.