Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.
The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.
Widemann
Brigitte C
BC
Pediatric Oncology Branch, Pediatric Oncology Branch, National Cancer Institute, 10 Center Dr., Bldg. 10, Rm. 13C103, Bethesda, MD 20892-1920, USA. bw42y@nih.gov
Balis
Frank M
FM
Shalabi
Aiman
A
Boron
Matthew
M
O'Brien
Michelle
M
Cole
Diane E
DE
Jayaprakash
Nalini
N
Ivy
Percy
P
Castle
Valerie
V
Muraszko
Karin
K
Moertel
Christopher L
CL
Trueworthy
Robert
R
Hermann
Robert C
RC
Moussa
Ali
A
Hinton
Stuart
S
Reaman
Gregory
G
Poplack
David
D
Adamson
Peter C
PC
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D001943:Breast Neoplasms / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004322:Drainage; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D008508:Medication Errors; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D008875:Middle Aged; D009369:Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011994:Recombinant Proteins / Q000627:therapeutic use; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate