PREVENTION OF IFOSFAMIDE NEPHROTOXICITY BY N- ACETYLCYSTEINE: CLINICAL PHARMACOKINETIC CONSIDERATIONS

Nancy Chen; Katarina Aleksa; Cindy Woodland; Michael Rieder; Gideon Koren

Nancy Chen

Department of Physiology and Pharmacology, University of Western Ontario, London, Canada

Katarina Aleksa

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada;

Cindy Woodland

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada; department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Canada.

Michael Rieder

Department of Physiology and Pharmacology, University of Western Ontario, London, Canada:Department of Paediatrics, University of Western Ontario, London, Canada:CIHR- GSK Chair in Paediatric Clinical Pharmacology, Children’s Hospital of Western Ontario, London, Canada

Gideon Koren

Department of Physiology and Pharmacology, University of Western Ontario, London, Canada; Ivey Chair in Molecular Toxicology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada;Department of Paediatrics, University of Western Ontario, London, Canada; Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada; department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Canada.

Keywords

Ifosfamide, N-acetylcysteine, nephrotoxicity, steady state concentration, pharmacokinetics, total body clearance, clinical relevance

Abstract

Background

Ifosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4mM prevents ifosfamide-induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical.

Objective

The aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations.

Methods

A systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted.

Results

The steady state concentrations of NAC administered intravenously to humans ranged from 0.04mM to 0.9mM and the urine concentration of NAC was 2mM.

Conclusion

This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.

Abstract 596 | PDF Downloads 94

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Published

Dec 8, 2018

How to Cite

Chen, N., Aleksa, K., Woodland, C., Rieder, M., & Koren, G. (2018). PREVENTION OF IFOSFAMIDE NEPHROTOXICITY BY N- ACETYLCYSTEINE: CLINICAL PHARMACOKINETIC CONSIDERATIONS. Journal of Population Therapeutics and Clinical Pharmacology, 14(2). Retrieved from https://www.jptcp.com/index.php/jptcp/article/view/161