A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function
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The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations.
Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; 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 AUC0-τ, CLR, and CLNR/F.
The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19–75%) over a dosage interval. When CLR increased due to improved renal function, AUC0-τ decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 × 100 to obtain median AUC0–12 of 18–26 mg/L/h for metformin IR and AUC0–24 of 38–51 mg/L/h for metformin XR, with Cmax < 5 mg/L.
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.
KeywordsMetformin Pharmacokinetics Population modelling Renal clearance Kidney disease Type 2 diabetes mellitus
This work was performed using computing infrastructure provided by the Australian Centre of Pharmacometrics. The Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy.
JKD designed and conducted studies 1 and 2, analysed the data, built the model and wrote the manuscript. MK conducted study 3, analysed the data and contributed to the manuscript. SSK and CMK provided advice on the population model and interpretation of the results. GG was involved in detailed discussions on the clinical significance of the results with JKD. All authors reviewed the manuscript and approved the final version of the manuscript.
Compliance with ethical standards
Informed consent was obtained from all individual participants included in the study. Studies 1 and 2 were approved by the Human Research Ethics Committee at St. Vincent’s Hospital and University of New South Wales, Sydney (08209/SVH08/035; 09280/SVH09/080), and were registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000908932). Study 3 was approved by the Ethics Committee of the University Medical Center Groningen (Almelo, The Netherlands; METc 2013.178).
This study was funded by the NH&MRC Program Grant 568612, Australian Research Council Grant LP 0990670 and St Vincent’s Clinic Foundation Sister Mary Bernice Research Grant. JKD and SSK had support from the Australian Research Council (ARC) Linkage Grant LP 0990670 for the submitted work.
The authors declare that they have no conflicts of interest.
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