Glucarpidase for Injection (Voraxaze®)
February 15, 2012
Pharmacology Update
Glucarpidase for Injection (Voraxaze®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A drug has been approved to treat high plasma levels of methotrexate. Glucarpidase is a bacterial enzyme produced by recombinant DNA technology using genetically modified Exherichia coli. Glucarpidase is a carboxypeptidase enzyme that metabolizes methotrexate to its inactive metabolites. It is marketed by BTG International Inc. as Voraxaze.
Indications
Glucarpidase is indicated for treatment of toxic plasma methotrexate levels (> 1 umol/L) in patients with delayed clearance of methotrexate due to renal impairment.1 It is not indicated in patients with normal or mildly impaired renal function as this may result in subtherapeutic levels of methotrexate.
Dosage
Glucarpidase is administered as a single intravenous injection of 50 units per kg.
Glucarpidase is available as lyophilized powder in 1000 units per vial.
Potential Advantages
Glucarpidase produces clinically important reduction in methotrexate plasma levels.1,2
Potential Disadvantages
Anti-glucarpidase antibodies developed in 17% of patients administered glucarpidase.1 Adverse events include paresthesia, flushing, and nausea/vomiting. The frequencies reported were 2%.1
Comments
The efficacy of glucarpidase was evaluated in a single-arm, open-label study in patients with significantly delayed methotrexate clearance secondary to renal dysfunction with preglucarpidase levels > 1 umol/L.1 This was defined as more than two standard deviations greater than the mean excretion curve for methotrexate. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR). This was defined as attaining < 1 umol/L within 15 minutes and sustained for up to 8 days post injection. Ten of 22 patients achieved RSCIR and 10 of 13 with baseline levels of methotrexate between 1 and 50 umol/L achieved RSCIR. Of the patients who did not achieve RSCIR, nine had baseline levels > 50 umol/L. For patients with levels < 1 umol/L after the first dose, a second dose did result in RSCIR. There are no data to indicate whether glucarpidase prevents fatal methotrexate toxicity.1 Early intervention, < 96 hours, in combination with leucovorin appears to be an effective strategy.2
Clinical Implications
Methotrexate is a commonly used anticancer drug and high-dose followed by leucovorin rescue is frequently used. In spite of measures to reduce the risk of potentially life-threatening methotrexate-induced renal toxicity (e.g., alkalization, hydration, pharmacokinetically guided leucovorin rescue), these still occur, albeit infrequently.3 Glucarpidase provides an important addition to leucovorin for the management of toxic levels of methotrexate.
References
1. Voraxaze Prescribing Information. West Conshohocken, PA: BTG International Inc.; January 2012.
2. Widemann BC, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome. J Clin Oncol 2010;28:3979-3986.
3. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006; 11:694-703.