VORAXAZE (Glucarpidase) - réduction de la concentration plasmatique toxique de méthotrexate

Key points

Favourable opinion for reimbursement as treatment to reduce toxic plasma methotrexate concentration in adults and children with delayed methotrexate elimination or at risk of methotrexate toxicity.

What therapeutic improvement?

Therapeutic improvement in the management of the condition.

Role in the care pathway?

In all cases of use of high-dose methotrexate (MTX HD), it is necessary to promote its elimination using hyperhydration, to stop medicinal products that could reduce methotrexate clearance (nonsteroidal anti-inflammatories, penicillin and its derivatives, salicylates, probenecid, gemfibrozil, trimethoprim-sulfamethoxazole, amphotericin, aminoglycosides, proton pump inhibitors) and urine alkalinisation and to implement close monitoring of kidney function and methotrexate concentrations.

The administration of folinic acid (calcium folinate or levofolinate), which works by displacing intracellular methotrexate into the blood compartment and helping to restore low intracellular folate reserves, is recommended 24 to 36 hours after treatment with MTX-HD until the elimination of MTX, with the dosage regimen being strongly dependent on the dosage, the patient’s renal function and plasma methotrexate concentrations. However, it should be noted that treatment with folinic acid is less effective at high concentrations of MTX (> 10 µmol/L for ≥ 48 hours), requiring a dose increase. Nonetheless, its use is limited by the maximum administrable dose, due to the high calcium content, exposing patients to a risk of cardiac and neurological disorders. Finally, renal dialysis methods may be considered. Standard haemodialysis and peritoneal dialysis have not been shown to be effective in the elimination of methotrexate. High-flow haemodialysis, haemoperfusion and acute intermittent haemodialysis using a high-flow dialyser have demonstrated efficacy on methotrexate clearance. However, these methods are not an optimal treatment solution given the pharmacokinetic characteristics of methotrexate, exposing patients to a risk of MTX concentration rebound phenomena.

Role of the medicinal product in the care pathway

VORAXAZE (glucarpidase) is a rescue treatment that should be used to reduce toxic methotrexate concentrations when patients have delayed methotrexate elimination or present a risk of methotrexate toxicity, defined as impaired renal function or evidence of delayed MTX elimination.

It should be noted that in 2018, an international expert consensus published specific guidelines for the use of glucarpidase in acute renal failure leading to delayed MTX elimination. The main recommendations include:

• The administration of glucarpidase (at a dose of 50 U/kg) should be performed within 48 to 60 hours following the start of MTX HD infusion, in order to limit toxicities;
• The administration of glucarpidase should be performed following an interval of 2 hours after the last folinic acid infusion in order to prevent any interactions, since the latter is a glucarpidase substrate in the same way as MTX;
• The administration of folinic acid should be resumed and continued for at least 2 hours following the administration of glucarpidase until MTX concentrations are below 0.1-0.2 µmol/L;
• Calcium levofolinate or disodium levofolinate should be preferred to calcium folinate in order to reduce the administered dose and calcium concentrations;
• The assay of residual methotrexate concentrations after glucarpidase should be performed using an HPLC method enabling the chromatographic separation of MTX and DAMPA (its main metabolite), to avoid any interference (this is not the case with other immunoenzymatic assay methods);
• Assay of plasma methotrexate concentrations and the administration of folinic acid should be continued for at least 48 hours following the administration of glucarpidase due to the MTX release phenomenon and the risk of rebound toxicity;
• Following MTX infusion, toxicity is expected when the plasma concentrations exceed the following limits (associated with elevated serum creatinine):
  • At the dose of 1 to 8 g/m2 administered for 24 to 42 hours: concentrations > 120 µmol/L at 24h, > 30 µmol/L at 36h, > 10 µmol/L at 42h and > 5 µmol/L at 48h
  • At the dose of 8 to 12 g/m2 administered for ≤ 6 hours: concentrations > 50 µmol/L at 24h, > 30 µmol/L at 36h, > 10 µmol/L at 42h and > 5 µmol/L at 48h
•  If glucarpidase is not available:
  • Treatment with folinic acid remains the best option to be used within 60 hours following the start of infusion of MTX HD;
  • In the event of high MTX concentrations, certain renal dialysis methods may be considered, with the expected benefits outweighing the risks associated with these techniques.