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

doi:10.1007/s00228-018-2552-z

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

Environmental and Occupational Health Sciences Institute

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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/m ² ]. 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.

Original language	American English
Pages (from-to)	51-57
Number of pages	7
Journal	European Journal of Clinical Pharmacology
Volume	75
Issue number	1
DOIs	https://doi.org/10.1007/s00228-018-2552-z
State	Published - Jan 18 2019

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

Keywords

Biomarkers
Cisplatin
Nephrotoxicity
Pharmacokinetics

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10.1007/s00228-018-2552-z

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Ibrahim, M. E., Chang, C., Hu, Y., Hogan, S. L., Mercke, N., Gomez, M., O’Bryant, C. L., Bowles, D. W., George, B., Wen, X., Buckley, B., Aleksunes, L., & Joy, M. S. (2019). Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients. European Journal of Clinical Pharmacology, 75(1), 51-57. https://doi.org/10.1007/s00228-018-2552-z

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title = "Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients",

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/m 2 ]. 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 = "Biomarkers, Cisplatin, Nephrotoxicity, Pharmacokinetics",

author = "Ibrahim, {Mustafa E.} and Cara Chang and Yichun Hu and Hogan, {Susan L.} and Nickie Mercke and Madeleine Gomez and O{\textquoteright}Bryant, {Cindy L.} and Bowles, {Daniel W.} and Blessy George and Xia Wen and Brian Buckley and Lauren Aleksunes and Joy, {Melanie S.}",

note = "Publisher Copyright: {\textcopyright} 2018, Springer-Verlag GmbH Germany, part of Springer Nature.",

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doi = "10.1007/s00228-018-2552-z",

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T1 - Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients

AU - Ibrahim, Mustafa E.

AU - Chang, Cara

AU - Hu, Yichun

AU - Hogan, Susan L.

AU - Mercke, Nickie

AU - Gomez, Madeleine

AU - O’Bryant, Cindy L.

AU - Bowles, Daniel W.

AU - George, Blessy

AU - Wen, Xia

AU - Buckley, Brian

AU - Aleksunes, Lauren

AU - Joy, Melanie S.

PY - 2019/1/18

Y1 - 2019/1/18

N2 - 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/m 2 ]. 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.

AB - 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/m 2 ]. 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.

KW - Biomarkers

KW - Cisplatin

KW - Nephrotoxicity

KW - Pharmacokinetics

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JO - European Journal of Clinical Pharmacology

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ER -

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

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