Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function.
OBJECTIVE
The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, administration, and current role in therapy of a recently approved agent for controlling methotrexate toxicity are reviewed.


CONCLUSIONS
Glucarpidase is a bacterial enzyme useful in reversing toxicity induced by the widely used antineoplastic agent methotrexate. Glucarpidase gained U.S. marketing approval in 2012 for reducing serum methotrexate concentrations greater than 1 μM/L in patients with delayed methotrexate clearance due to impaired renal function. In clinical trials, glucarpidase has been administered to a total of 3887 patients receiving high-dose methotrexate (i.e., doses of ≥500 mg/m(2)), including pediatric patients. Patients treated with glucarpidase in addition to standard supportive care (hydration, urinary alkalization, leucovorin rescue, and, in some cases, hemodialysis) had a mean reduction in serum methotrexate levels of greater than 88%, with reductions occurring in a median of 15 minutes; however, up to 4.4% of adult patients and up to 6% of pediatric patients in clinical trial cohorts died despite glucarpidase use, suggesting the agent might not confer a survival advantage over supportive care alone. Glucarpidase is well tolerated; the most common adverse effects are flushing, nausea, vomiting, hypotension, and headache, which are typically grade 1 or 2 in severity and resolve without intervention.


CONCLUSIONS
Glucarpidase is a well-tolerated and effective treatment for reducing serum methotrexate concentrations greater than 1 μM/L in patients with impaired renal function. While there are few adverse effects associated with treatment, there may be little or no impact on methotrexate-associated mortality.
Mariana Fermiano is B.S.Pharmacy Candidate, State University of Campinas, Sao Paulo, Brazil. Jason Bergsbaken, Pharm.D., is Postgraduate Year 2 Hematology/Oncology Pharmacy Resident, University of Wisconsin (UW) Hospital and Clinics, Madison. Jill M. Kolesar, Pharm.D., BCPS, FCCP, is Professor, School of Pharmacy, UW-Madison, and Faculty Supervisor, Analytical Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics, UW Carbone Comprehensive Cancer Center, Madison.
Mariana
M
Fermiano
Jason
J
Bergsbaken
Jill M
JM
Kolesar
D000964:Antimetabolites, Antineoplastic / Q000097:blood*; D006801:Humans; D008727:Methotrexate / Q000097:blood*; D051437:Renal Insufficiency / Q000378:metabolism*; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate