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

Authors: Ibrahim, Mustafa E; Chang, Cara; Hu, Yichun; Hogan, Susan L; Mercke, Nickie; Gomez, Madeleine; O'Bryant, Cindy L; Bowles, Daniel W; George, Blessy; Wen, Xia; Buckley, Brian; Aleksunes, Lauren; Joy, Melanie S

Published In Eur J Clin Pharmacol, (2019 Jan)

Abstract: 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.

PubMed ID: 30220072

MeSH Terms: Acute Kidney Injury/chemically induced*; Aged; Antineoplastic Agents/administration & dosage*; Antineoplastic Agents/adverse effects; Antineoplastic Agents/pharmacokinetics; Biomarkers/urine; Cisplatin/administration & dosage*; Cisplatin/adverse effects; Cisplatin/pharmacokinetics; Creatinine/blood; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neoplasms/drug therapy*; Regression Analysis