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Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity.

Methods

Participants [n = 13] were treated with a 1-h cisplatin infusion [30–75 mg/m2]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity.

Results

Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, β2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate.

Conclusions

Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

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Acknowledgements

The authors wish to thank the participants in this study.

Funding

Grant funding support for this study was provided by National Institutes of Health funding numbers T32ES007148, R21DK093903, P30ES005022, and P30CA072720.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 12850 E. Montview Blvd, Mail Stop C238, Room V20-4108, Aurora, CO, 80045, USA

    Mustafa E. Ibrahim, Cara Chang, Nickie Mercke, Madeleine Gomez, Cindy L. O’Bryant & Melanie S. Joy

  2. Kidney Center, University of North Carolina School of Medicine, Division of Nephology and Hypertension, Chapel Hill, NC, 27516, USA

    Yichun Hu & Susan L. Hogan

  3. Cancer Center, University of Colorado, Anschutz Medical Campus, 1665 Aurora Ct, Aurora, CO, 80045, USA

    Cindy L. O’Bryant, Daniel W. Bowles & Melanie S. Joy

  4. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Davidson Hall, 96 Davidson Rd, Piscataway, NJ, 08854, USA

    Blessy George, Xia Wen & Lauren Aleksunes

  5. Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ, 08854, USA

    Brian Buckley & Lauren Aleksunes

  6. Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, School of Medicine, 13001 E 17th Pl, Aurora, CO, 80045, USA

    Melanie S. Joy

Authors
  1. Mustafa E. Ibrahim
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  2. Cara Chang
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  3. Yichun Hu
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  4. Susan L. Hogan
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  5. Nickie Mercke
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  6. Madeleine Gomez
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  7. Cindy L. O’Bryant
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  8. Daniel W. Bowles
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  9. Blessy George
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  10. Xia Wen
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  11. Brian Buckley
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  12. Lauren Aleksunes
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  13. Melanie S. Joy
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Contributions

MI analyzed data and wrote the manuscript. CC, NM, MG, CLO, and DWB contributed to conduct of the patient study. YH and SLH contributed to the analysis plan. BG, XW, and BB performed biomarker assays and/or platinum analyses. MSJ and LA conceived, designed and conducted the study, and oversaw all components of the analytical and manuscript plan. All authors contributed to editing the manuscript.

Corresponding author

Correspondence to Melanie S. Joy.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Ibrahim, M.E., Chang, C., Hu, Y. et al. Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients. Eur J Clin Pharmacol 75, 51–57 (2019). https://doi.org/10.1007/s00228-018-2552-z

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  • DOI: https://doi.org/10.1007/s00228-018-2552-z

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