Mechanism of Action

Voraxaze® Works in the Circulation to Quickly Clear MTX1-3

Voraxaze® and Leucovorin Work Synergistically

For patients receiving HDMTX therapy, intracellular leucovorin (LV) is critical to provide a source of tetrahydrofolates and restore DNA synthesis to prevent damage to normal cells.

However, LV does not help reduce circulating concentrations of MTX, which can remain dangerously high in patients with delayed MTX clearance due to impaired renal function.

Voraxaze® rapidly cleaves MTX into 2 inactive metabolites to provide a nonrenal pathway for elimination.1,4

 
Watch the video to see how Voraxaze® works extracellularly.4
  1. Exogenous tetrahydrofolates (LV) must compete with MTX for cellular uptake via the RFC. At higher MTX concentrations, LV may be less effective.4

  2. MTX is polyglutamated after entering cells and reversibly inhibits DHFR, leading to a significant reduction in DNA and RNA biosynthesis.4

  3. LV provides intracellular rescue following MTX by providing a source of tetrahydrofolate to restore DNA and RNA synthesis despite ongoing inhibition of DHFR via MTX.4

  4. Voraxaze® eliminates extracellular MTX via rapid enzymatic breakdown to nontoxic DAMPA and glutamate. Voraxaze® should be given in conjunction with LV to provide both intracellular and extracellular rescue from unwanted HDMTX toxicity.1,4

Abbreviations: =
5-FU 5-formylpteroate
CH2THF 5,10-methylenetetrahydrofolate
DAMPA 4-deoxy-4-amino-N10-methylpteroic acid
DHF dihydrofolate
DHFR dihydrofolate reductase
dUMP deoxyuridine monophosphate
dTMP deoxythymidine monophosphate
FPGS folylpolyglutamate synthase
GLU glutamate
LV leucovorin
MTX methotrexate
RFC reduced folate carrier
SHMT1 serine hydroxymethyltransferase-1
THF tetrahydrofolate
TYMS thymidylate synthase

References

  1. Voraxaze® [prescribing information]. BTG International Inc; 2013.
  2. Howard SC, et al. Preventing and managing toxicities of high-dose methotrexate. The Oncologist 2016; 21:1-12.
  3. Widemann BC, Balis FM, Kim A, 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.
  4. 2013 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT), Clinical Toxicology 2013; 51(7):575-724. doi:10.3109/15563650.2013.817658.
  5. Ramsey L, Balis FM, O’Brien MM, et al. Consensus guidelines for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Durham, NC. The Oncologist. 2017 Oct 27. doi: 10.1634/theoncologist.2017-0243
  6. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11:694-703
  7. Schwartz S, Borner K,Müller K, et al. Glucarpidase (carboxypeptidase G2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-1308.
  8. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100:2222-2232
  9. Data on file. BTG International Inc. 2012.
  10. de Miguel D, García-Suárez J Martín Y, Gil-Fernández JJ, Burgaleta C. Severe acute renal failure following high-dose methotrexate therapy in adults with haematological malignancies: a significant number result from unrecognized co-administration of several drugs. Nephrol Dial Transplant. 2008;23:3762-3766.
  11. Jahnke K, Korfel A, Martus P, et al; on behalf of the German Primary Central Nervous System Lymphoma Study Group (G-PCNSL-SG). High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol. 2005;16:445-449
  12. Flombaum C, Meyers P. High-dose leucovorin as sole therapy for methotrexate toxicity. Journal of Clinical Oncology 1999; 17(5): 1589-1594.
  13. Murashima M, et al. Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report. Am J Kidney Dis 2009; 53:781-874.
  14. Wall S, Johansen M, et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 1996; 28(6):846-854.
  15. Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2018;71(3):314-325.
  16. Green JM. Glucarpidase to combat toxic levels of methotrexate in patients. Ther Clin Risk Manag. 2012;8:403-4
  17. Glucarpidase (Voraxaze®) National Drug Monograph and Considerations for Use. U.S. Department of Veterans Affairs website. 2014. http://www.pbm.va.gov/clinicalguidance/drugmonographs/Glucarpidase_ Drug_Monograph_and_Considerations_for_Use.doc. Published June 2014. Accessed November 04, 2016.
  18. Leucovorin [prescribing information]. Bedford Laboratories; 2011.