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

Fluids Barriers CNS. 2017 Oct 3;14(1):26. doi: 10.1186/s12987-017-0075-0.


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 1200 mg/kg NAC. 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 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15).

Results: The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/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 2-3 mM 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 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: . Unique identifier: 2011-000887-92.

Keywords: Chemoprotection; Cisplatin; Clinical trial; N-Acetylcysteine; Nephrotoxicity; Ototoxicity.

Publication types

  • Clinical Trial

MeSH terms

  • Acetylcysteine / administration & dosage*
  • Acetylcysteine / adverse effects
  • Acetylcysteine / pharmacokinetics
  • Aged
  • Antineoplastic Agents / adverse effects*
  • Cisplatin / adverse effects*
  • Dose-Response Relationship, Drug
  • Female
  • Free Radical Scavengers / administration & dosage*
  • Free Radical Scavengers / adverse effects
  • Free Radical Scavengers / pharmacokinetics
  • Humans
  • Infusions, Intravenous
  • Injections, Intra-Arterial
  • Male
  • Maximum Tolerated Dose*
  • Middle Aged
  • Renal Insufficiency


  • Antineoplastic Agents
  • Free Radical Scavengers
  • Cisplatin
  • Acetylcysteine