Methotrexate elimination – glucarpidase
Anticancer drug methotrexate has several other applications, including the treatment of autoimmune diseases
Anticancer drug methotrexate has several other applications, including the treatment of autoimmune diseases. However, one of the potential side-effects of high doses is kidney failure. If methotrexate levels do rise, then the result can be damage to the liver and the kidneys, ulcerative stomatitis and a low white blood cell count, among others.
Glucarpidase, or carboxypeptidase G2, is an enzyme being developed by BTG that cleaves methotrexate into non-toxic metabolites, and thus has the potential to reverse the build-up of the toxic drug in the body. In a trial 43 patients on a high dose of methotrexate, and with methotrexate serum concentrations of 1–1.187µmol/l, were given glucarpidase, plus the standard treatment of leucovorin rescue guided by methotrexate immunoassay.1
The treatment was well tolerated, giving an immediate reduction in serum concentrations of methotrexate of at least 97%. While 10 of the 43 patients died as a result of complications with the high dose therapy, all bar three of the group had either normalisation or improvement of their serum creatinine. The researchers suggested that earlier recognition of delayed methotrexate elimination and more rapid intervention are desirable.
In another trial, 135 patients with high dose methotrexate induced nephrotoxicity were given glucarpidase, leucovirin rescue by continuous intravenous infusion, either with or without additional doses of thymidine.2 Plasma methotrexate concentrations decreased within 15 minutes of glucarpidase treatment commencing, and of 12 deaths six were directly attributed to irreversible methotrexate toxicity. Severe toxicity and mortality occurred in patients where glucarpidase rescue was delayed. The enzyme was given orphan drug designation because of the lack of treatment options for this group of patients, and in January the US FDA gave it marketing approval for this group of patients.
references
1. S. Schwartz et al. Oncologist, 2007, 12, 1299
2. B.C. Widemann et al. J. Clin. Oncol. 2010, 28, 3979
