Treatment of Accidental Intrathecal Methotrexate Overdose With Intrathecal Carboxypeptidase G₂

Authors: Brigitte C. Widemann¹; Frank M. Balis²; Aiman Shalabi²; Matthew Boron²; Michelle O'Brien¹; Diane E. Cole²; Nalini Jayaprakash¹; Percy Ivy³; Valerie Castle²; Karin Muraszko²; Christopher L. Moertel⁴; Robert Trueworthy²; Robert C. Hermann²; Ali Moussa³; Stuart Hinton²; Gregory Reaman²; David Poplack²; Peter C. Adamson²

Source: Journal of the National Cancer Institute, Volume 96, Number 20, 20 October 2004 , pp. 1557-1559(3)

Publisher: Oxford University Press

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Abstract:

The bacterial enzyme carboxypeptidase G<INF>2</INF> (CPDG<INF>2</INF>) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG<INF>2</INF> (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<INF>2</INF> administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG<INF>2</INF> administration, the median concentrations of methotrexate in CSF were 264 mgr

M (range = 97–510 mgr

M) among patients who had CSF exchange and 8050 mgr

M (range = 2439–16 500 mgr

M) among patients who did not. After intrathecal CPDG<INF>2</INF> 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<INF>2</INF> were not detected in plasma after treatment with intrathecal CPDG<INF>2</INF>. Intrathecal CPDG<INF>2</INF> is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.

Document Type: Research article

DOI: 10.1093/jnci/djh270

Affiliations: 1: Affiliations of authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD (BCW, FMB, MOB, DEC, NJ); Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD (AS, MB, PI); University of Michigan, Ann Arbor (VC, KM); Children's Hospital and Clinics St. Paul, St. Paul, MN (CLM); University of Kansas Medical Center, Kansas City (RT); Northwest Georgia Oncology Centers, PC, Marietta, GA (RCH); Hillcrest Medical Center, Tulsa, OK (AM); Kansas City Cancer Center, Kansas City, MO (SH); Children's Oncology Group, Arcadia, CA (GR); Texas Children's Cancer Center, Houston (DP); Children's Hospital of Philadelphia, Philadelphia, PA (PCA) 2: Affiliations of authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD (BCW, FMB, MOB, DEC, NJ); Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD (AS, MB, PI); University of Michigan, Ann Arbor (VC, KM); Children's Hospital and Clinics St. Paul, St. Paul, MN (CLM); University of Kansas Medical Center, Kansas City (RT); Northwest Georgia Oncology Centers, PC, Marietta, GA (RCH); Hillcrest Medical Center, Tulsa, OK (AM); Kansas City Cancer Center, Kansas City, MO (SH); Children's Oncology Group, Arcadia, CA (GR); Texas Children's Cancer Center, Houston (DP); Children's Hospital of Philadelphia, Philadelphia, PA (PCA) 3: Affiliations of authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD (BCW, FMB, MOB, DEC, NJ); Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD (AS, MB, PI); University of Michigan, Ann Arbor (VC, KM); Children's Hospital and Clinics St. Paul, St. Paul, MN (CLM); University of Kansas Medical Center, Kansas City (RT); Northwest Georgia Oncology Centers, PC, Marietta, GA (RCH); Hillcrest Medical Center, Tulsa, OK (AM); Kansas City Cancer Center, Kansas City, MO (SH); Children's Oncology Group, Arcadia, CA (GR); Texas Children's Cancer Center, Houston (DP); Children's Hospital of Philadelphia, Philadelphia, PA (PCA) 4: Affiliations of authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD (BCW, FMB, MOB, DEC, NJ); Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD (AS, MB, PI); University of Michigan, Ann Arbor (VC, KM); Children's Hospital and Clinics St. Paul, St. Paul, MN (CLM); University of Kansas Medical Center, Kansas City (RT); Northwest Georgia Oncology Centers, PC, Marietta, GA (RCH); Hillcrest Medical Center, Tulsa, OK (AM); Kansas City Cancer Center, Kansas City, MO (SH); Children's Oncology Group, Arcadia, CA (GR); Texas Children's Cancer Center, Houston (DP); Children's Hospital of Philadelphia, Philadelphia, PA (PCA)

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