Successful Treatment of Delayed Methotrexate Clearance Using Glucarpidase Dosed on Ideal Body Weight in Obese Patients

Abstract

Delayed methotrexate (MTX) elimination after treatment with high-dose (HD) MTX may result in lifethreatening toxicities as well as acute kidney injury (AKI). Treatment includes administration of glucarpidase, an enzyme that rapidly inactivates MTX. Dosing of glucarpidase is based on body weight; however, recommendations for dosage adjustments in obese patients are lacking. We describe three obese adult patients (body mass index [BMI] range 31-43 kg/m 2 ) who received HD-MTX following all precautions for its treatment. Although peak MTX concentrations were within the expected range (308-368 µmol/L), MTX concentrations after 24 hours or later were markedly increased (97, 52, and 19 µmol/L, respectively). Two patients experienced AKI. After a single intravenous dose of glucarpidase 4000 units (50 units/kg on the basis of ideal body weight [IBW]) was administered to each patient 38, 46, and 60 hours, respectively, after the start of MTX, MTX concentrations dropped quickly to 1.37, 0.07, and 0.03 µmol/L, respectively, and further decreased steadily. Over time, clinical status and renal function improved in all patients. Glucarpidase is a highly hydrophilic molecule with a volume of distribution of 3.6 L, representing the intravascular volume of an adult. Therefore, we used IBW for glucarpidase dose calculations, allowing us to reduce the dose that would have been determined by using total body weight. This approach resulted in a rapid decrease of MTX serum concentrations and may reduce treatment costs of this highly expensive drug. KEY WORDS glucarpidase, methotrexate, high dose, obesity. (Pharmacotherapy 2020;40(5):479-483)

Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury

“…The dose of 50 U/kg as recommended in the prescribing information has been shown to efficiently reduce MTX plasma levels which is used as surrogate parameter for clinical outcome [9,14,22,23]. Few case series advocate that MTX plasma levels can be efficiently reduced even with glucarpidase doses lower than 50 U/kg [9][10][11][12][13][14]. Besides, dose reductions are a valuable mean to reduce the financial burden of this very costly treatment [13].…”

“…Few case series advocate that MTX plasma levels can be efficiently reduced even with glucarpidase doses lower than 50 U/kg [9][10][11][12][13][14]. Besides, dose reductions are a valuable mean to reduce the financial burden of this very costly treatment [13].…”

“…However, detailed efficacy data were not provided [7]. Other reports, mainly in pediatric patients, suggested that doses < 50 U/kg (minimum 7.5 U/kg) might be equally effective in lowering MTX levels [9][10][11][12][13][14]. Apart from the application of a fixed dose per bodyweight, it has been discussed to adjust glucarpidase to MTX concentration.…”

“…The recommended dose of glucarpidase is 50 U/kg; however this has not been formally established by a dose finding study in humans. Small numbers of case series suggest that glucarpidase might be effective at lower quantities [9][10][11][12][13][14]. Considering the high costs of the drug, dose reduction strategies also have the potential to significantly reduce the financial burden for this rescue treatment.…”