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 μM (range = 97-510 μM) among patients who had CSF exchange and 8050 μM (range = 2439-16500 μM) 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.