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

  • Mustafa E. Ibrahim
  • Cara Chang
  • Yichun Hu
  • Susan L. Hogan
  • Nickie Mercke
  • Madeleine Gomez
  • Cindy L. O’Bryant
  • Daniel W. Bowles
  • Blessy George
  • Xia Wen
  • Brian Buckley
  • Lauren Aleksunes
  • Melanie S. Joy
Pharmacokinetics and Disposition
  • 26 Downloads

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.

Keywords

Cisplatin Pharmacokinetics Biomarkers Nephrotoxicity 

Notes

Acknowledgements

The authors wish to thank the participants in this study.

Author 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.

Funding information

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

Compliance with ethical standards

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.

Supplementary material

228_2018_2552_MOESM1_ESM.docx (19 kb)
ESM 1 (DOCX 19 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mustafa E. Ibrahim
    • 1
  • Cara Chang
    • 1
  • Yichun Hu
    • 2
  • Susan L. Hogan
    • 2
  • Nickie Mercke
    • 1
  • Madeleine Gomez
    • 1
  • Cindy L. O’Bryant
    • 1
    • 3
  • Daniel W. Bowles
    • 3
  • Blessy George
    • 4
  • Xia Wen
    • 4
  • Brian Buckley
    • 5
  • Lauren Aleksunes
    • 4
    • 5
  • Melanie S. Joy
    • 1
    • 3
    • 6
  1. 1.Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado, Anschutz Medical CampusAuroraUSA
  2. 2.Kidney Center, University of North Carolina School of Medicine, Division of Nephology and HypertensionChapel HillUSA
  3. 3.Cancer CenterUniversity of Colorado, Anschutz Medical CampusAuroraUSA
  4. 4.Department of Pharmacology and Toxicology, Ernest Mario School of PharmacyRutgers UniversityPiscatawayUSA
  5. 5.Environmental and Occupational Health Sciences InstituteRutgers UniversityPiscatawayUSA
  6. 6.Division of Renal Diseases and HypertensionUniversity of Colorado, Anschutz Medical Campus, School of MedicineAuroraUSA

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