What is the recommended dose and administration of glucarpidase (carboxypeptidase G2) for managing methotrexate toxicity?

Glucarpidase for Managing Methotrexate Toxicity

The recommended dose of glucarpidase for managing methotrexate toxicity is 50 units/kg administered as a single intravenous injection over 5 minutes, which rapidly reduces plasma methotrexate concentrations by approximately 99%. This intervention is specifically indicated for patients with delayed methotrexate clearance due to renal dysfunction.

Indications for Glucarpidase

• Glucarpidase is indicated for patients with toxic plasma methotrexate concentrations (>1 μmol/L) in the presence of impaired kidney function 1
• It should be administered as soon as possible after methotrexate overdose or when delayed clearance is detected, as earlier administration leads to better outcomes 2
• Primary indication is for high-dose methotrexate toxicity with renal injury, and it is also indicated for intrathecal methotrexate poisoning 2

Dosing and Administration Protocol

• Administer 50 units/kg as a single intravenous injection over 5 minutes 1
• Should be given as early as possible, ideally within 48-60 hours of methotrexate administration for optimal efficacy 1
• A single dose is typically sufficient to achieve a 99% reduction in plasma methotrexate levels 1

Mechanism of Action

• Glucarpidase is a recombinant bacterial enzyme with high affinity for methotrexate 2
• It rapidly hydrolyzes methotrexate to inactive metabolites, allowing for non-renal clearance 1
• Reduces serum methotrexate concentrations by 90-95% within 15 minutes of administration 2

Monitoring After Administration

• Continue monitoring methotrexate levels after glucarpidase administration 1
• Note that immunoassay methods may be unreliable for 48 hours after glucarpidase; high-performance liquid chromatography (HPLC) is preferred for accurate measurement 1
• Monitor renal function until recovery, as 64% of patients with renal impairment recover to normal function at a median of 12.5 days after glucarpidase administration 1

Concurrent Therapies

• Continue leucovorin (folinic acid) rescue therapy even after glucarpidase administration 3
• Maintain hydration and urine alkalinization until methotrexate levels decrease to <0.1 μmol/L 3
• Temporarily suspend leucovorin administration for 2 hours before and after glucarpidase administration, as glucarpidase also hydrolyzes leucovorin 2

Important Considerations and Caveats

• Glucarpidase is significantly more effective than hemodialysis for rapid reduction of methotrexate levels 4
• Limited availability and high cost may restrict access in some settings 2
• In cases where glucarpidase is not available, hemodialysis can be considered as an alternative, though less effective option 4
• Glucarpidase does not address intracellular methotrexate, so continued leucovorin therapy is essential 1

Clinical Efficacy

• Rapid and sustained clinically important reduction in plasma methotrexate concentration is achieved in approximately 59% of patients 1
• A single dose typically reduces methotrexate levels by 99% within minutes 1
• Particularly valuable in patients with severe renal dysfunction where methotrexate elimination would otherwise be significantly delayed 3