N-acetylcysteine as a novel prophylactic treatment for ifosfamide-induced nephrotoxicity in children: translational pharmacokinetics.
Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM·h (range, 9.92-30.02 mM·h), compared to the mean systemic exposure found in treated children (14.48 mM·h; range, 6.22-32.96 mM·h). They also report 2 pediatric cases in which NAC-attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children.
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Lauren N
LN
Hanly
Nancy
N
Chen
Katarina
K
Aleksa
Murray
M
Cutler
Milica
M
Bajcetic
Rasmi
R
Palassery
Osvaldo
O
Regueira
Curtis
C
Turner
Bandar
B
Baw
Becky
B
Malkin
David
D
Freeman
Michael J
MJ
Rieder
Tetyana L
TL
Vasylyeva
Gideon
G
Koren
D000082:Acetaminophen / Q000633:toxicity; D000111:Acetylcysteine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000293:Adolescent; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D002648:Child; D062787:Drug Overdose / Q000188:drug therapy; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D020011:Protective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D018712:Analgesics, Non-Narcotic; D018906:Antineoplastic Agents, Alkylating; D020011:Protective Agents; D000082:Acetaminophen; D007069:Ifosfamide; D000111:Acetylcysteine