TY - JOUR
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, Tamás
AU - Molnár, Gabriella
AU - Kapocsi, Judit
AU - Merkely, Béla
AU - Fu, Rongwei
AU - Doolittle, Nancy D.
AU - Tóth, Gerda B.
AU - Urdang, Zachary
AU - Neuwelt, Edward A.
N1 - Publisher Copyright:
© 2017 The Author(s).
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.
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.
KW - Chemoprotection
KW - Cisplatin
KW - Clinical trial
KW - N-Acetylcysteine
KW - Nephrotoxicity
KW - Ototoxicity
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UR - http://www.scopus.com/inward/citedby.url?scp=85030309041&partnerID=8YFLogxK
U2 - 10.1186/s12987-017-0075-0
DO - 10.1186/s12987-017-0075-0
M3 - Article
C2 - 28974245
AN - SCOPUS:85030309041
SN - 2045-8118
VL - 14
JO - Fluids and Barriers of the CNS
JF - Fluids and Barriers of the CNS
IS - 1
M1 - 26
ER -