Document Type

Poster

Publication Date

12-3-2012

Abstract

Presented at: ASHP Clinical MidYear Meeting in Las Vegas.

Background

Methotrexate (MTX)

  • Cytotoxic agent that competitively inhibits dihydrofolate reductase (DHFR), the intracellular enzyme responsible for converting folic acid to reduced folate inhibitors, necessary for DNA synthesis
  • Used since 1948 in the treatment of various malignancies and as a disease-modifying agent in rheumatoid arthritis and psoriasis
  • High-dose mexthotrexate (HDMTX) began in 1960s solely or in combination with other chemotherapeutic agents

Methotrexate Toxicity

  • Almost exclusively cleared through the kidneys
    • Precipitation of drug occurs in the renal tubules
    • Prolonged elevations of systemic MTX concentrations results in potential serious toxicity
  • Increased use of HDMTX resulted in recognizable toxicities
    • Myelosuppression
    • Mucositis
    • Nephrotoxicity
    • Acute hepatitis
    • Fatal toxicity à secondary to renal failure or sepsis

Prevention of Methotrexate Toxicity

  • Hydration
  • Alkalinization of urine
    • Sodium bicarbonate administration for urine pH ≥ 7
  • Leucovorin
    • Counteracts cellular damage caused by MTX as it is converted to tetrahydrofolate, a precursor of DNA synthesis
    • Does NOT reduce the amount of circulating MTX

Glucarpidase (Voraxaze®)

  • An enzyme produced in Escherichia Coli that hydrolyzes the carboxyl terminal glutamate from folic acid and its analogues, including MTX, resulting in inactive metabolites
  • Offers an alternative to rapidly reducing the amount of MTX in systemic circulation
  • Evaluated in 3 clinical studies à produced a clinically important reduction (CIR) in MTX concentrations in majority of patients (72/116, 62%)
    • Most frequently reported adverse events: allergic reaction and non-allergic paraesthesia

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