Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients
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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.
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.
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.
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.
KeywordsCisplatin Pharmacokinetics Biomarkers Nephrotoxicity
The authors wish to thank the participants in this study.
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.
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.
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.
- 3.Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 120(4):c179–c184Google Scholar
- 5.Dieterle F, Sistare F, Goodsaid F, Papaluca M, Ozer JS, Webb CP, Baer W, Senagore A, Schipper MJ, Vonderscher J, Sultana S, Gerhold DL, Phillips JA, Maurer G, Carl K, Laurie D, Harpur E, Sonee M, Ennulat D, Holder D, Andrews-Cleavenger D, Gu YZ, Thompson KL, Goering PL, Vidal JM, Abadie E, Maciulaitis R, Jacobson-Kram D, Defelice AF, Hausner EA, Blank M, Thompson A, Harlow P, Throckmorton D, Xiao S, Xu N, Taylor W, Vamvakas S, Flamion B, Lima BS, Kasper P, Pasanen M, Prasad K, Troth S, Bounous D, Robinson-Gravatt D, Betton G, Davis MA, Akunda J, McDuffie JE, Suter L, Obert L, Guffroy M, Pinches M, Jayadev S, Blomme EA, Beushausen SA, Barlow VG, Collins N, Waring J, Honor D, Snook S, Lee J, Rossi P, Walker E, Mattes W (2010) Renal biomarker qualification submission: a dialog between the FDA-EMEA and predictive safety testing consortium. Nat Biotechnol 28(5):455–462CrossRefGoogle Scholar
- 6.Shinke H, Masuda S, Togashi Y, Ikemi Y, Ozawa A, Sato T, Kim YH, Mishima M, Ichimura T, Bonventre JV, Matsubara K (2015) Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients. Cancer Chemother Pharmacol 76(5):989–996CrossRefGoogle Scholar
- 7.Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV (2010) Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 28(5):478–485CrossRefGoogle Scholar
- 12.Nagai N, Kinoshita M, Ogata H, Tsujino D, Wada Y, Someya K, Ohno T, Masuhara K, Tanaka Y, Kato K, Nagai H, Yokoyama A, Kurita Y (1996) Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients. Cancer Chemother Pharmacol 39(1–2):131–137CrossRefGoogle Scholar
- 13.Skali H, Uno H, Levey AS, Inker LA, Pfeffer MA, Solomon SD (2011) Prognostic assessment of estimated glomerular filtration rate by the new chronic kidney disease epidemiology collaboration equation in comparison with the modification of diet in renal disease study equation. Am Heart J 162(3):548–554CrossRefGoogle Scholar
- 19.Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A, NGAL Meta-analysis Investigator Group (2009) Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 54(6):1012–1024CrossRefGoogle Scholar
- 21.Fukushima K, Okada A, Sasaki K, Kishimoto S, Fukushima S, Hamori M, Nishimura A, Shibata N, Shirai T, Terauchi R, Kubo T, Sugioka N (2016) Population pharmacokinetic-toxicodynamic modeling and simulation of cisplatin-induced acute renal injury in rats: effect of dosing rate on nephrotoxicity. J Pharm Sci 105(1):324–332CrossRefGoogle Scholar