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

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, ß2M, 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, ß2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, ß2M, 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.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.