Glucarpidase (voraxaze), a carboxypeptidase enzyme for methotrexate toxicity.

Methotrexate (MTX) is a folic acid antagonist used for its antiproliferative and anti-inflammatory activity, either as a stand-alone drug or in combination with other medications, in the treatment of neoplastic and autoimmune diseases (Table 1).1,2 Folic acid plays a crucial role in the synthesis of DNA and cell replication.2 In the dihydrofolate reductase (DHFR) pathway, tetrahydrofolate (THF) is the active form of folic acid.2 THF donates carbon groups that are eventually used for synthesizing deoxyribose purines (i.e., adenosine and guanosine) and pyrimidines (specifically thymidine) that constitute human DNA.2,3 Table 1 FDA-Approved Indications for Methotrexate Because MTX also affects noncancerous cells, treatment may lead to adverse drug effects (ADEs) and undesirable toxicities.4 MTX can crystallize and precipitate in the kidney, especially at higher systemic concentrations and in the presence of acidic urine.5 Neither hemodialysis (HD) nor peritoneal dialysis (PD) sufficiently removes the drug from circulation, whereas continuous venovenous hemodialysis(CVVHD) seems to be the most efficacious dialysis method.5,6 Leucovorin (LV), or folinic acid (citrovorum factor), is a rescue agent that exerts its effects via competitive cellular uptake, but it does not sufficiently reduce toxic levels of MTX.7 The standard-of-care regimen combines LV with continuous urinary alkalinization (with sodium bicarbonate) and rigorous hydration.8 Unfortunately, even with normal pretreatment renal function, this approach does not reverse nephrotoxicity in 2% to 10% of patients.9