BRIEF COMMUNICATION

Treatment of Accidental Intrathecal Methotrexate Overdose With Intrathecal Carboxypeptidase G2

Brigitte C. Widemann, Frank M. Balis, Aiman Shalabi, Matthew Boron, Michelle O'Brien, Diane E. Cole, Nalini Jayaprakash, Percy Ivy, Valerie Castle, Karin Muraszko, Christopher L. Moertel, Robert Trueworthy, Robert C. Hermann, Ali Moussa, Stuart Hinton, Gregory Reaman, David Poplack, Peter C. Adamson

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)

Correspondence to: Brigitte C. Widemann, MD, Pediatric Oncology Branch, National Cancer Institute, 10 Center Dr., Bldg. 10, Rm. 13C103, Bethesda, MD 20892-1920 (e-mail: bw42y{at}nih.gov)


    ABSTRACT
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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 = 2439–16 500 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.


Intrathecal methotrexate at doses of 6 to 15 mg is widely used to treat and prevent leptomeningeal tumor spread. Accidental intrathecal methotrexate overdoses, which result from medication preparation errors or when methotrexate prescribed for systemic administration is administered intrathecally, are rare but can cause severe or fatal toxicity (14). The severity of acute neurotoxicity and patient outcomes after accidental intrathecal methotrexate overdoses depend on the administered dose and the rapidity and effectiveness of attempts to remove methotrexate from the subarachnoid space (5,6). The current treatment options for methotrexate overdoses are cerebrospinal fluid (CSF) drainage by lumbar puncture, ventriculolumbar CSF perfusion, and administration of systemic corticosteroids and leucovorin (7,8).

Carboxypeptidase G2 (CPDG2) is a bacterial enzyme that hydrolyzes methotrexate to its inactive metabolites, 4-deoxy-4-amino-N10-methylpteroic acid and glutamate (9). Intravenous administration of recombinant CPDG2 has been shown to rapidly lower plasma levels of methotrexate in patients who have delayed methotrexate clearance because of renal dysfunction (10,11). In addition, intrathecal CPDG2 rescued nonhuman primates from intrathecal methotrexate overdoses by hydrolyzing methotrexate in CSF within minutes (12).

Patients who received accidental intrathecal methotrexate overdoses (i.e., doses >100 mg) were enrolled in a collaborative National Cancer Institute, Pediatric Oncology Branch/Children's Oncology Group multi-institutional protocol (n = 4) or a compassionate-use Cancer Therapy Evaluation Program protocol (n = 3). On the basis of federal regulations (21 CFR 50.23), institutional review boards deferred or waived informed-consent requirements a priori for administration of intrathecal CPDG2 in the setting of an unplanned emergency. Written informed consent for collection and analysis of pharmacokinetic samples was obtained from all subjects after CPDG2 administration.

Recombinant CPDG2 was manufactured by the Centre for Applied Microbiology and Research (Porton Down, Salisbury, U.K.) and provided by the Pharmaceutical Management Branch of the Cancer Therapy Evaluation Program in vials that contained 1000 U of lyophilized enzyme. The intrathecal dose of CPDG2 (2000 U reconstituted in 12 mL of normal saline) was administered immediately after reconstitution over a period of 5 minutes.

Standard treatment for patients who experienced intrathecal methotrexate overdoses included lumbar puncture to remove methotrexate from CSF by drainage, ventricular catheter placement and ventriculolumbar perfusion (when feasible) to remove methotrexate by CSF exchange in cases of continued or worsening neurologic toxicity, intrathecal administration of CPDG2, intravenous administration of leucovorin (four doses of 100 mg every 6 hours) to prevent systemic methotrexate toxicity, and intravenous administration of dexamethasone (four doses of 4 mg every 6 hours) to minimize methotrexate-induced chemical arachnoiditis.

We measured the methotrexate concentrations in CSF before and 1, 24, and 48 hours after administration of intrathecal CPDG2 by using a previously described reverse-phase high-performance liquid chromatography method, for which the lower limit of quantification was 0.1 µM (10,11). All CSF specimens were heated to more than 80 °C for 5 minutes to inactivate CPDG2. The amount of methotrexate removed by lumbar drainage before CPDG2 administration was calculated by multiplying the volume of CSF removed by the concentration of methotrexate in CSF. Commercially available assays were used by the participating institutions to monitor plasma methotrexate concentrations on a daily basis. We used a previously described enzyme-linked immunoadsorbent method (which we modified by using a goat anti–human immunoglobulin and an alkaline phosphatase–labeled rabbit anti–goat immunoglobulin G [Kirkegaard and Perry Laboratories, Gaithersburg, MD]) to measure levels of antibodies to CPDG2 in plasma collected from patients, when possible, on days 3, 7, and 14 after administration of intrathecal CPDG2 (12).

Seven patients (median age = 9 years; range = 5–77 years) with acute lymphoblastic leukemia (n = 4), non-Hodgkin lymphoma (n = 2), or breast cancer (n = 1) were treated with intrathecal CPDG2 after receiving an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155–600 mg) administered via lumbar route (n = 5) or an Ommaya reservoir (n = 2) (Table 1). The first patient entered on this protocol (patient 1 in Tables 1 and 2) was previously reported (2) and is also included in this series. Methotrexate overdoses resulted from medication preparation errors (n = 4) or from intrathecal administration of methotrexate that was originally prescribed for systemic administration (n = 3). Five of the seven patients developed severe toxicity within 1 hour of the intrathecal methotrexate overdose; symptoms included seizures (n = 5), coma (n = 2), severe cardiopulmonary compromise (n = 2), confusion (n = 2), tachycardia (n = 2), hypertension (n = 2), severe headache (n = 1), intense back pain (n = 1), and nausea and vomiting (n = 1). Patient 3, who received 196 mg of methotrexate and had immediate diagnosis and treatment of the overdose, was sedated and remained asymptomatic. Patient 5, who received 364 mg of methotrexate, developed only sacral numbness and mild headache.


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Table 1. Characteristics of patients who received intrathecal carboxypeptidase G2 for accidental intrathecal methotrexate overdoses (doses > 100 mg)*

 

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Table 2. Pharmacokinetics of methotrexate in cerebrospinal fluid after intrathecal administration of carboxypeptidase G2*

 
Patients 1–6 underwent lumbar or Ommaya reservoir CSF drainage at a median of 1.8 hours after the methotrexate overdose (range = 0–3.5 hours). Patients 2 and 3 received CPDG2 via a ventriculostomy followed by ventriculolumbar perfusion 1 and 1.5 hours, respectively, after intrathecal administration of CPDG2. In other patients, ventriculolumbar perfusion (patient 1), CSF exchange via Ommaya reservoir followed by ventriculolumbar perfusion (patient 6), CSF exchange via lumbar catheter (patient 4) or Ommaya reservoir (patient 7), or continued CSF drainage via lumbar catheter (patient 5) was performed before administration of intrathecal CPDG2. Warmed normal saline (n = 4), 5% albumin solution (n = 1), or Elliott's B solution (QOL Pharmaceutical, Woodenville, WA) (n = 1) were used for CSF exchange.

CPDG2 was administered via lumbar route (n = 2), ventriculostomy (n = 2), Ommaya reservoir (n = 2), or lumbar route and ventriculostomy (n = 1) at a median of 5 hours (range = 3–9 hours) after intrathecal methotrexate overdose. No toxic effects were attributed to CPDG2. Four patients had a CSF white blood cell count of 0–4 cells/µL 1–4 days after the overdose.

CSF drainage removed 32%–58% of the methotrexate dose in four patients (patients 1, 4, 6, and 7; data not shown). CSF methotrexate concentrations were lower in the four patients who underwent CSF exchange before receiving CPDG2 than in the three patients who did not (Table 2). Intrathecal CPDG2 treatment resulted in a rapid and profound (>98%) decrease in CSF methotrexate concentrations (Table 2). The CSF methotrexate concentrations at 24 hours after intrathecal CPDG2 ranged from 0.29 to 0.65 µM (n = 5), which is similar to the range of CSF concentrations among patients 24 hours after they have received a standard 12-mg dose of intrathecal methotrexate (13,14). The plasma methotrexate concentration (n = 6) within 24 hours of the overdose ranged from 0.18 to 1.0 µM. Antibodies to CPDG2 were not detected in plasma (n = 3) after intrathecal CPDG2.

All patients recovered completely from the methotrexate overdose (median recovery time = 7 days; range = 0–21 days), with the exception of general and short-term memory impairment in patients 6 and 7, respectively. Three patients with acute lymphoblastic leukemia later received additional treatment with intrathecal methotrexate without complications.

Although the contribution of CPDG2 to the favorable outcome in these patients cannot be precisely determined, its lack of toxicity and the rapidity and completeness with which it hydrolyzes methotrexate in CSF (12) suggest that intrathecal CPDG2 is beneficial for patients who receive intrathecal methotrexate overdoses. Preventing intrathecal methotrexate overdoses remains the best approach to avoiding methotrexate toxicity, but on-site availability of CPDG2 should be considered for the treatment of accidental intrathecal methotrexate overdoses because intrathecal CPDG2 rapidly eliminates methotrexate from CSF and serves as an effective adjunct to ventriculolumbar perfusion or lumbar drainage.


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P. C. Adamson is a consultant for Protherics, Inc. (Brentwood, TN), which is continuing development of CPDG2.

We thank Dr. Dale Shoemaker, the pharmacists of the Cancer Therapy Evaluation Program, National Cancer Institute, and Dr. Roger Melton of Enact Pharma, Salisbury, U.K., for their efforts in making CPDG2 available for investigational use.

CPDG2 is available via a clinical trial of the Pediatric Oncology Branch, National Cancer Institute (NCI), and the Children's Oncology Group, and for compassionate use via the Cancer Therapy Evaluation Program of the NCI (Pharmaceutical Management Branch, phone: 301-496-5725).


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Manuscript received February 23, 2004; revised July 27, 2004; accepted August 3, 2004.


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