Glucarpidase to combat toxic levels of methotrexate in patients

Abstract

In January 2012, glucarpidase (Voraxaze®) received approval from the US Food and Drug Administration for intravenous treatment of toxic plasma methotrexate concentrations due to impaired renal clearance. Methotrexate, an antifolate agent, has been used for over 60 years in the treatment of various cancers. High-dose methotrexate has been particularly useful in the treatment of leukemias and lymphomas. However, even with aggressive hydration and urine alkalinization, such regimens can lead to acute renal dysfunction, as indicated by decreases in urine production and concomitant increases in blood urea nitrogen and serum creatinine levels. Because methotrexate is largely excreted by the kidneys, this can greatly potentiate tissue damage. Toxic levels of blood methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase. Glucarpidase is a recombinant form of carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to form the amino acid glutamate and 2,4-diamino-N10-methylpteroic acid. Catabolites of methotrexate are much less toxic than the parent compound, and are primarily excreted by hepatic mechanisms. Glucarpidase has been available on a compassionate basis since the 1990s, and a variety of case reports and larger clinical trials have demonstrated the safety and efficacy of this drug in patients ranging in age from infants to the elderly and in a variety of races and ethnic groups. Glucarpidase should not be administered within 2 hours of leucovorin, because this agent is a reduced folate which competes with methotrexate for the enzyme and glucarpidase inactivates leucovorin. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective. Future applications of this enzyme in chemotherapy continue to be an active area of research.

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

“…2 Currently, it is commercially available as a product manufactured with recombinant DNA technology using genetically modified Escherichia coli. 5 Glucarpidase has a high affinity for folate analogs, including leucovorin and methotrexate, with MichaelisMenten constant values in the 10-to 20-mM range.…”

“…2014; 71:793-8 M ethotrexate is a folic acid analog frequently used to treat a variety of cancers and nonmalignant disorders. [1][2][3] High-dose methotrexate, defined as doses of at least 500 mg/m 2 , is used to treat some cancers, including acute lymphoblastic leukemia, meningeal leukemia, non-Hodgkin's lymphoma, and osteosarcoma. 1,4 Patients receiving high-dose methotrexate require aggressive hydration, alkalization of the urine, and leucovorin rescue to minimize the risk of therapy-related toxicity.…”

“…1,4 Patients receiving high-dose methotrexate require aggressive hydration, alkalization of the urine, and leucovorin rescue to minimize the risk of therapy-related toxicity. 1,2 Methotrexate and its metabolites are renally eliminated; therefore, high doses, which are more likely to cause nephrotoxicity, can also result in the inability to excrete methotrexate and may lead to prolonged exposure to toxic concentrations, typically defined as serum methotrexate concentrations greater than 1 mM/L. 1,2 This may result in further nephrotoxicity, hepatotoxicity, myelotoxicity, mucositis, neurological symptoms, and death in some cases.…”

“…1,2 Methotrexate and its metabolites are renally eliminated; therefore, high doses, which are more likely to cause nephrotoxicity, can also result in the inability to excrete methotrexate and may lead to prolonged exposure to toxic concentrations, typically defined as serum methotrexate concentrations greater than 1 mM/L. 1,2 This may result in further nephrotoxicity, hepatotoxicity, myelotoxicity, mucositis, neurological symptoms, and death in some cases. 4,5 In a review of clinical trial data on 3887 patients with osteosarcoma receiving high-dose methotrexate, the rate of renal toxicity was 1.8%, with three fatalities attributed to methotrexate toxicity.…”

Enzymes Approved for Human Therapy: Indications, Mechanisms and Adverse Effects

“…Glucarpidase is indicated in such patients, ensuring that methotrexate is eliminated enzymatically, mainly by hepatic mechanisms, and not by the kidneys. Toxic blood levels of the drug can be rapidly decreased by intravenous administration of glucarpidase [85]. Leucovorin, a reduced folate and potential substrate for glucarpidase, should not be given with the enzyme that degrades it.…”