Glucarpidase

Glucarpidase Brand Name– VORAXAZE

What is Glucarpidase

Glucarpidase is an intravenous carboxypeptidase enzyme approved to reduce toxic plasma methotrexate concentrations (greater than 1 micromol/L) in adults and pediatric patients with delayed methotrexate clearance (greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function.

The drug is not indicated for use in patients who exhibit the expected clearance of methotrexate or in patients with normal or mildly impaired renal function. The likelihood of achieving a plasma methotrexate concentration of 1 micromol/L or less 15 minutes after glucarpidase receipt and maintained for up to 8 days appears to be correlated with the methotrexate concentration before glucarpidase receipt.

For example, the endpoint was reached in 77% of patients (n = 13) with a baseline methotrexate concentration greater than 1 but less than 50 micromol/L as compared with 0% of patients (n = 9) with a higher baseline plasma concentration.

However, all patients with a baseline methotrexate concentration greater than 50 micromol/L had more than a 95% rapid reduction in methotrexate concentration that was maintained up to 8 days after glucarpidase receipt.

Indications

• methotrexate toxicity

For the treatment of methotrexate toxicity (methotrexate plasma concentration greater than 1 micromole/liter) in patients with delayed methotrexate clearance due to impaired renal function

NOTE: Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate defined as plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered.

NOTE: Glucarpidase is not indicated for use in patients with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate

Side Effects

1. anaphylactic shock
2. anaphylactoid reactions
3. antibody formation
4. blurred vision
5. diarrhea
6. flushing
7. flushing
8. headache
9. hypertension
10. hypotension
11. infusion-related reactions
12. nausea
13. paresthesias
14. rash
15. throat irritation
16. tremor
17. vomiting

Monitoring Parameters

• serum creatinine/BUN

Contraindications

• breast-feeding
• pregnancy

Interactions

• Leucovorin
• Levoleucovorin
• Pemetrexed
• Pralatrexate

Mechanism of Action

Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from methotrexate and, thus, provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.

As a result of its enzymatic action, glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate.⁴⁸³⁰⁴

Pharmacokinetics

Glucarpidase is administered intravenously. After receipt of 50 units/kg IV over 5 minutes to healthy patients, the mean systemic clearance was 7.5 mL/minute. Serum glucarpidase activity levels declined with a mean elimination half-life of 5.6 hours.

The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer half-life of 9 hours.

After receipt of glucarpidase 50 units/kg to 22 patients with methotrexate toxicity, the methotrexate concentration measured by a chromatographic method was reduced by at least 97% within 15 minutes in everyone and was maintained at a more than 95% reduction up to 8 days in 20 of the patients.⁴⁸³⁰⁴