Limited sampling strategy for determining metformin area under the plasma concentration-time curve

AIM: The aim was to develop and validate limited sampling strategy (LSS) models to predict the area under the plasma concentration-time curve (AUC) for metformin.

METHODS: Metformin plasma concentrations (n = 627) at 0-24 h after a single 500 mg dose were used for LSS development, based on all subsets linear regression analysis. The LSS-derived AUC(0,24 h) was compared with the parameter 'best estimate' obtained by non-compartmental analysis using all plasma concentration data points. Correlation between the LSS-derived and the best estimated AUC(0,24 h) (r(2) ), bias and precision of the LSS estimates were quantified. The LSS models were validated in independent cohorts.

RESULTS: A two-point (3 h and 10 h) regression equation with no intercept estimated accurately the individual AUC(0,24 h) in the development cohort: r(2) = 0.927, bias (mean, 95% CI) -0.5, -2.7-1.8% and precision 6.3, 4.9-7.7%. The accuracy of the two point LSS model was verified in study cohorts of individuals receiving single 500 or 1000 mg (r(2) = -0.933-0.934) or seven 1000 mg daily doses (r(2) = 0.918), as well as using data from 16 published studies covering a wide range of metformin doses, demographics, clinical and experimental conditions (r(2) = 0.976). The LSS model reproduced previously reported results for effects of polymorphisms in OCT2 and MATE1 genes on AUC(0,24 h) and renal clearance of metformin.

CONCLUSIONS: The two point LSS algorithm may be used to assess the systemic exposure to metformin under diverse conditions, with reduced costs of sampling and analysis, and saving time for both subjects and investigators.