Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency

Edit Dósa, Krisztina Heltai, Tamás Radovits, Gabriella Molnár, Judit Kapocsi, Béla Merkely, Rongwei Fu, Nancy D. Doolittle, Gerda B. Tóth, Zachary Urdang, Edward A. Neuwelt

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background: Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. Methods: Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200mg/kgNAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15min post NAC. Twenty-eight subjects (15 men; mean age 72.2±6.8years) received NAC IV (N=13) or IA (N=15). Results: The first participant to experience grade 4 toxicity was at the 600mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p<0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3mM concentration which seemed to be nephroprotective in previous preclinical studies. Conclusions: In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu. Unique identifier: 2011-000887-92

Original languageEnglish (US)
Article number26
JournalFluids and Barriers of the CNS
Volume14
Issue number1
DOIs
StatePublished - Oct 3 2017

Keywords

  • Chemoprotection
  • Cisplatin
  • Clinical trial
  • N-Acetylcysteine
  • Nephrotoxicity
  • Ototoxicity

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

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