Treatment of Accidental Intrathecal Methotrexate Overdose With Intrathecal Carboxypeptidase G ₂

Abstract

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