FDA Approves Glucarpidase to Reduce Toxic Methotrexate Levels

Roxanne Nelson

January 17, 2012

January 17, 2012 — The US Food and Drug Administration (FDA) has approved glucarpidase (Voraxaze, BTG International Inc) as a treatment for the rapid and sustained reduction of toxic methotrexate levels due to impaired renal function.

Methotrexate, a common chemotherapeutic agent, is often given in high doses to treat or prevent the recurrence of a number of malignancies, including leukemia, lymphoma, and osteosarcoma. Normally excreted by the kidneys, patients may be at risk for methotrexate toxicity if their renal function is impaired or if they have evidence of delayed methotrexate elimination.

"Prolonged exposure to high levels of methotrexate can result in kidney and liver damage, severe mouth sores, damage to the lining of the intestine, skin rashes, and death due to low blood counts," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. "Voraxaze is an important new treatment option for cancer patients aimed at preventing these toxicities associated with sustained high levels of methotrexate."

Glucarpidase is a recombinant enzyme that is able to rapidly decrease serum levels of methotrexate and thus reduce its concentration in most patients to below the threshold for serious toxicity. It lowers systemic methotrexate levels by rapidly causing methotrexate to convert to glutamate and 4-deoxy-4-amino-N 10-methylpteroic acid (DAMPA). Compared with methotrexate, DAMPA is 25 to 100 times less potent an inhibitor of dihydrofolate reductase (DHFR) and is significantly less cytotoxic.

Both DAMPA and glutamate undergo hepatic metabolism, and this provides an alternative route of methotrexate elimination.

Glucarpidase is administered intravenously and has been granted orphan drug status in the United States and the European Union.

In a clinical trial that included 22 patients, administration of glucarpidase decreased the methotrexate level to below a critical level within 15 minutes; levels stayed at that point for 8 days. Of this cohort, 10 patients achieved this standard. Although this result was not observed in all patients, glucarpidase was effective at eliminating 95% of the methotrexate in all patients.

A separate study evaluated the drug's safety in 290 patients who were experiencing high serum levels of methotrexate. The most common adverse events, observed in greater than 1% of patients participating in the trial, included hypotension, headache, nausea, vomiting, flushing, and paraesthesia.