Abstract
BackgroundCisplatin 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.MethodsDue 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).ResultsThe 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.ConclusionsIn 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: https://eudract.ema.europa.eu. Unique identifier: 2011-000887-92
Highlights
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
By determining the maximum tolerated dose (MTD) we potentially gain the maximum concentration of NAC in the brain and cochlea to diminish the toxicity of agents like cisplatin, the entry of NAC may be limited by the blood–brain barrier (BBB) and blood-labyrinth barrier
In an animal study performed by our group, we found that when radiolabeled NAC was administered IA into the right carotid artery of the rat, high levels of radiolabel were found throughout the right cerebral hemisphere, regardless of whether or not the BBB was opened
Summary
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, no clinical phase I trial was performed before. Cisplatin is a common chemotherapeutic agent used to treat various types of malignant tumors Side effects such as neuro-, oto-, and nephrotoxicity limit the application of cisplatin. Several oto- and nephroprotective approaches were developed (such as hydrating the patients during treatment, using less toxic cisplatin analogues) to avoid these reactions, including various chemoprotective agents used in experimental models (dimethylthiourea, melatonin, selenium, vitamin E, N-acetylcysteine [NAC], sodium thiosulfate) [5, 7,8,9,10,11,12,13]
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