Treatment of Accidental Intrathecal Methotrexate Overdose With Intrathecal Carboxypeptidase G sub(2)

The bacterial enzyme carboxypeptidase G sub(2) (CPDG sub(2)) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG sub(2) (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 CPDG sub(2) administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG sub(2) administration, the median concentrations of methotrexate in CSF were 264 kM (range = 97-510 kM) among patients who had CSF exchange and 8050 kM (range = 2439-16 500 kM) among patients who did not. After intrathecal CPDG sub(2) 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 CPDG sub(2) were not detected in plasma after treatment with intrathecal CPDG sub(2). Intrathecal CPDG sub(2) is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.