Glucarpidase (Voraxaze)

Background

Glucarpidase (Voraxaze), manufactured by BTG International, is a carboxypeptidase FDA approved for the treatment of toxic plasma methotrexate concentrations (>1 mcmol/L) in adult and pediatric patients with decreased methotrexate clearance associated with impaired renal function. Voraxaze is also utilized for the off-label indication of rescue treatment due to accidental overdose of intrathecal methotrexate.^1-3

Pharmacology/ Pharmacokinetics

Glucarpidase is a recombinant bacterial enzyme that works by hydrolyzing methotrexate and its metabolites to inactive metabolites that are metabolized by the liver, allowing for a nonrenal pathway for drug elimination. The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in 8 subjects with normal renal function by administering intravenous (IV) injection of 50 units/kg over 5 minutes. Serum glucarpidase levels declined, with a mean elimination half-life of 5.6 hours and a mean systemic clearance of 7.5 mL/min. The mean C_max was 3.3 mcg/mL and the mean area under the curve (AUC) was 23.3 mcg·h/mL. Data for subjects with renal impairment were similar except for a longer half-life of 8.2 hours as compared with 5.6 hours in healthy subjects.^1,2

Dosing

Glucarpidase is administered via IV injection as a single dose of 50 units/ kg administered over 5 minutes. The IV line should be flushed before and after each dose. Glucarpidase should only be given when a patient is determined to have a toxic methotrexate plasma concentration greater than 1 mcmol/L. No dosing adjustments are needed in patients with renal impairment.^1,3 For the off-label use of accidental intrathecal overdose, 2000 units of glucarpidase has been shown to be efficacious.^1-3

Clinical Efficacy

Widemann et al performed a retrospective study of 100 cancer patients who received glucarpidase, leucovorin, and in some cases thymidine for treatment of renal failure induced by highdose methotrexate. Sixty-five patients received 1 glucarpidase dose, 28 received 2 glucarpidase doses 24 hours apart, and 7 received 3 glucarpidase doses every 4 hours. Plasma methotrexate concentrations decreased by 98% within 15 minutes of injection of glucarpidase. Investigators concluded that early intervention with leucovorin and glucarpidase was highly effective in the treatment of renal failure induced by high-dose methotrexate, and that repeated use of glucarpidase was possible.⁴

In 2011, researchers at St. Jude Children’s Research Hospital performed a retrospective study of pediatric cancer patients treated with high-dose methotrexate between 1998 and 2010. The goal of this study was to determine the safety of resuming treatment with methotrexate following rescue with glucarpidase. Of 20 children who received glucarpidase, 13 were later treated again with methotrexate. Although 1 patient suffered neurotoxicity with further methotrexate, renal function returned to baseline in all patients, and all survived treatment. The authors concluded that high-dose methotrexate treatment can be resumed after treatment with glucarpidase with close monitoring of renal function and plasma methotrexate concentrations.⁵

Medication Safety

Side effects of glucarpidase are rare, but include paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache. Serious allergic reactions, including anaphylaxis, have occurred rarely. Glucarpidase is classified as Pregnancy Category C.

Due to a potential interaction, leucovorin should not be administered 2 hours before or after a dose of glucarpidase. Leucovorin dosing should not be stopped when glucarpidase is administered; leucovorin must be continued until the concentration of methotrexate has been maintained below the leucovorin treatment threshold for a minimum of 3 days. While using glucarpidase, hydration and alkalinization of the urine should be continued as indicated.

Availability and Cost

Glucarpidase is available as preservative- free lyophilized powder for injection in a 1000-unit vial. Glucarpidase should be stored

at 36°F to 46°F (2°C to 8°C)

. Once reconstituted with 1 mL of normal saline for injection, the contents of the vial should be used immediately or stored under refrigeration for up to 4 hours. The acquisition cost of Voraxaze is $26,775 per 1000-unit vial. More information about Voraxaze is available at

www.voraxaze.com

.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She is currently the pharmacy and therapeutics secretary at UNCH and manages the day-to-day operations of the Drug Information Center and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy.

References:

• Voraxaze [package insert]. Brentwood, TN: BTG International Inc; January 2012.
• Green J. Glucarpidase to fight toxic levels of methotrexate in patients. Ther Clin Risk Man. 2012:8;403-413.
• Glucarpidase (Voraxaze) for methotrexate toxicity. Med Let Drugs Ther. 2012;54(1385):18-20.
• Widemann B, Balis F, Kim A, et al. Glucarpidase, leucovorin, and thiymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcomes. J Clin Oncol. 2010;28(25):3978-3986.
• Christensen A, Pauley J, Molinelli A, et al. Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients. Cancer. 2012;118(17):4321-4330.