A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function.

PURPOSE

The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CL), and apparent non-renal clearance of metformin (CL/F) in patients with varying degrees of kidney function and to develop dosing recommendations.

METHODS

Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CL; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC, CL, and CL/F.

RESULTS

The data (66 patients, 327 observations) were best described by a two-compartment model, and CL was a covariate for CL. Mean CL was 17 L/h (CV 22%) and mean CL/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CL increased due to improved renal function, AUC decreased proportionally, while CL/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CL/3 × 100 to obtain median AUC of 18-26 mg/L/h for metformin IR and AUC of 38-51 mg/L/h for metformin XR, with C < 5 mg/L.

CONCLUSIONS

The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.