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, T. Radovits, Gabriella Molnár, Judit Kapocsi, B. Merkely, Rongwei Fu, Nancy D. Doolittle, Gerda B. Tóth, Zachary Urdang, Edward A. Neuwelt

Research output: Contribution to journalArticle

5 Citations (Scopus)

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
Article number26
JournalFluids and Barriers of the CNS
Volume14
Issue number1
DOIs
Publication statusPublished - Oct 3 2017

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Acetylcysteine
Cisplatin
Renal Insufficiency
Maximum Tolerated Dose
Auditory Hair Cells
Pediatrics
Endovascular Procedures
Clinical Trials, Phase I
Educational Status
Medulloblastoma
Poisons
Inner Ear
Platinum
Serum
Chronic Renal Insufficiency
Neoplasms
Pharmacokinetics
Quality of Life
Clinical Trials

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

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

In: Fluids and Barriers of the CNS, Vol. 14, No. 1, 26, 03.10.2017.

Research output: Contribution to journalArticle

Dósa, Edit ; Heltai, Krisztina ; Radovits, T. ; Molnár, Gabriella ; Kapocsi, Judit ; Merkely, B. ; Fu, Rongwei ; Doolittle, Nancy D. ; Tóth, Gerda B. ; Urdang, Zachary ; Neuwelt, Edward A. / 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. In: Fluids and Barriers of the CNS. 2017 ; Vol. 14, No. 1.
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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",
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T1 - 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

AU - Dósa, Edit

AU - Heltai, Krisztina

AU - Radovits, T.

AU - Molnár, Gabriella

AU - Kapocsi, Judit

AU - Merkely, B.

AU - Fu, Rongwei

AU - Doolittle, Nancy D.

AU - Tóth, Gerda B.

AU - Urdang, Zachary

AU - Neuwelt, Edward A.

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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

AB - 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

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KW - Cisplatin

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KW - N-Acetylcysteine

KW - Nephrotoxicity

KW - Ototoxicity

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