Injectable Enzyme Clears Methotrexate Build Up in the Blood

A novel enzyme breaks down toxic plasma methotrexate (MTX) concentrations in chemotherapy patients with delayed clearance due to impaired renal function.

Injectable Glucarpidase, a product of BTG International (London, United Kingdom) is an experimental treatment for the rapid and sustained reduction of toxic MTX levels due to impaired renal function, which can lead to a delay in elimination of MTX from the body. The drug works by breaking down MTX into its inactive metabolites, which are then eliminated from the body by routes other than the kidney (primarily the liver).

The drug was approved by the US Food and Drug administration (FDA; Silver Spring, MD, USA) as an orphan drug, a designation applied to drugs and biologics treating conditions that affect fewer than 200,000 people, and which grants the marketer tax and marketing incentives. The approval was based on two studies, one measuring efficacy, and the other safety. The efficacy study involved 22 patients, and treatment was considered successful if a patient's MTX level fell below a critical level within 15 minutes and remained below a critical level for eight days. Of those treated, 10 patients hit the success benchmark; treatment eliminated 95% of the MTX in all 22 patients.

The safety study evaluated the drug in 290 patients, with the most common adverse events being hypotension, headache, nausea, and vomiting, flushing, and abnormal sensation. Glucarpidase is not indicated for use in patients who exhibit the expected clearance of MTX (plasma concentrations within two standard deviations of the mean MTX excretion curve specific for the dose of administered) or those with normal or mildly impaired renal function, due to the potential risk of subtherapeutic exposure to MTX.

“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 Center for Drug Evaluation and Research. “Voraxaze is an important new treatment option for cancer patients aimed at preventing these toxicities associated with sustained high levels of methotrexate.”

MTX is an antimetabolite and antifolate drug, used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions; it acts by inhibiting the metabolism of folic acid. High dose MTX chemotherapy is used to treat or prevent the recurrence of certain types of cancer in both adults and children, such as leukemia, lymphoma, and osteosarcoma.

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US Food and Drug administration