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

Janna K Duong, M. Y.A.M. Kroonen, S. S. Kumar, H L Heerspink, C. M. Kirkpatrick, G. G. Graham, K. M. Williams, R. O. Day

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: 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. 

Methods: 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. 

Results: 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. 

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.

Original languageEnglish
Pages (from-to)981–990
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Volume73
Issue number8
DOIs
Publication statusPublished - Aug 2017

Keywords

  • Kidney disease
  • Metformin
  • Pharmacokinetics
  • Population modelling
  • Renal clearance
  • Type 2 diabetes mellitus

Cite this

Duong, Janna K ; Kroonen, M. Y.A.M. ; Kumar, S. S. ; Heerspink, H L ; Kirkpatrick, C. M. ; Graham, G. G. ; Williams, K. M. ; Day, R. O. / A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function. In: European Journal of Clinical Pharmacology. 2017 ; Vol. 73, No. 8. pp. 981–990.
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abstract = "Purpose: 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. Methods: 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. Results: 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. 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.",
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A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function. / Duong, Janna K; Kroonen, M. Y.A.M.; Kumar, S. S.; Heerspink, H L; Kirkpatrick, C. M.; Graham, G. G.; Williams, K. M.; Day, R. O.

In: European Journal of Clinical Pharmacology, Vol. 73, No. 8, 08.2017, p. 981–990.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function

AU - Duong, Janna K

AU - Kroonen, M. Y.A.M.

AU - Kumar, S. S.

AU - Heerspink, H L

AU - Kirkpatrick, C. M.

AU - Graham, G. G.

AU - Williams, K. M.

AU - Day, R. O.

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N2 - Purpose: 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. Methods: 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. Results: 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. 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.

AB - Purpose: 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. Methods: 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. Results: 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. 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.

KW - Kidney disease

KW - Metformin

KW - Pharmacokinetics

KW - Population modelling

KW - Renal clearance

KW - Type 2 diabetes mellitus

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U2 - 10.1007/s00228-017-2251-1

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