Treatment of Accidental Intrathecal Methotrexate Overdose With Intrathecal Carboxypeptidase G2

Abstract

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.

Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function

“…The most important efficacy outcome is survival; the historical mortality rate in pediatric patients with methotrexateinduced nephrotoxicity treated with best supportive care, including dialysis, is 4.4%. 16 This morality rate is comparable to that reported in pediatric trials of glucarpidase and best supportive care, in which mortality ranged from 0 to 6%. 8,9 Given that dialysis-based approaches were allowed in all of these trials, it is unclear whether glucarpidase provides any survival benefit relative to best supportive care.…”

“…Glucarpidase has been administered intrathecally on an off-label basis for the treatment of accidental intrathecal methotrexate overdose. 16 Seven patients with a median age of nine years received 2000 units of glucarpidase intrathecally after intrathecal methotrexate overdoses of greater than 100 mg (median dose, 364 mg; range, 155-600 mg) a median of five hours after methotrexate administration (range, three to nine hours). Other standard treatments, including lumbar puncture, ventricular catheter placement, and i.v.…”

“…5 Risks associated with dialysis-based procedures include risks associated with insertion of vascular access devices, bleeding, infection, hypotension, and fluid and electrolyte imbalances. 16,19 Cost is an important consideration with glucarpidase therapy. The median wholesale price per 1,000-unit vial of glucarpidase is $28,350; this would equate to $113,400 for one therapeutic dose for a 70-kg patient (i.e., four vials).…”

Intracerebroventricular drug administration

“…[58] But glucarpidase (Voraxaze®), a recombinant form of carboxypeptidase G2 that enzymatically cleaves methotrexate, has been used to successfully treat patients with acute MTX toxicity after either intravenous or ICV administration. [59] …”

Spinal Muscular Atrophy

“…Human immunodeficiency virus (HIV) and pediatric leukemia, both once considered untreatable, now have several treatment choices available to patients and carry a much improved prognosis. [63][64][65][66] To replicate a similar success in SMA, patients and their advocacy groups can help by embracing clinical trials and by encouraging SMA families to participate. Trials with rapid recruitment avoid confounders such as a time effect, and can accelerate the overall rate of SMA drug development.…”