Glucarpidase

Glucarpidase is a recombinant bacterial enzyme used as an antidote to methotrexate (MTX). High-dose methotrexate is cleared mainly by the kidneys, so when renal function is impaired the drug stays at toxic levels in the blood. Glucarpidase provides a second, non-renal route of elimination.

Mechanism of Action

• Enzymatic action: glucarpidase hydrolyses the carboxyl-terminal glutamate residue from folic acid and structurally related molecules, including methotrexate. This converts methotrexate into glutamate and the inactive metabolite DAMPA (4-deoxy-4-amino-N10-methylpteroic acid).
• Alternative elimination: DAMPA and glutamate are both metabolised by the liver, so methotrexate can be removed in patients with kidney dysfunction during high-dose treatment.
• Outside the cells only: because of its large molecular size, glucarpidase does not cross cell membranes and so does not counteract the intracellular antineoplastic effect of high-dose methotrexate.
• Clinical evidence: in four open-label, single-arm compassionate-use studies in patients with delayed methotrexate elimination due to renal dysfunction, a clinically important reduction (all central HPLC methotrexate concentrations at or below 1 µmol/L after the first dose) was reached in 85.7% of the 28 patients with central data in Study 001 and 54.8% of the 84 in Study 002.

Pharmacokinetics

• Absorption and distribution: given intravenously. In healthy subjects, 50 Units/kg over 5 minutes gave a mean peak concentration of 3.3 µg/mL and a mean AUC of 23.3 µg·h/mL. Mean volume of distribution was 3.55 L.
• Metabolism: as a protein, glucarpidase is broken down to small peptides and amino acids, so classical biotransformation studies were not needed. In vitro, the metabolite DAMPA may induce CYP1A2 and CYP2C9, a modest effect expected only in the minority of patients with the highest DAMPA exposure.
• Elimination: serum enzyme activity fell with a mean half-life of 5.6 hours, and total glucarpidase concentration with a mean half-life of 9 hours; mean systemic clearance was 7.5 mL/min. DAMPA concentrations fall with a mean half-life of 8.6 hours. No clinically relevant accumulation was seen after a repeat injection within a methotrexate cycle.
• Special populations: in 4 subjects with severe renal impairment (creatinine clearance under 30 mL/min) the parameters were similar to those of healthy subjects. The effect of age has not been formally evaluated.

• Methotrexate toxicity: to reduce toxic plasma methotrexate concentration in adults and children (aged 28 days and older) with delayed methotrexate elimination or at risk of methotrexate toxicity.

• Hypersensitivity to glucarpidase or to any of the excipients (lactose, trometamol, zinc acetate dihydrate).

The most frequent related reactions were burning sensation, headache, paraesthesia, flushing and feeling hot. The frequency categories below come from pooled clinical data (489 patients) and post-marketing reports; see the SmPC for details.

Uncommon (≥1/1,000 to <1/100): burning sensation, headache, paraesthesia; flushing; feeling hot.

Rare (≥1/10,000 to <1/1,000): hypersensitivity; hypoaesthesia, somnolence, tremor; hypotension; pleural effusion, throat tightness; upper abdominal pain, diarrhoea, nausea, vomiting; pruritus, rash; pyrexia, rebound effect.

Very rare (<1/10,000): anaphylactic reaction; tachycardia; drug eruption, skin reaction; crystalluria (DAMPA crystalluria); infusion site reaction.

As with any intravenous protein product, infusion-related and hypersensitivity reactions are possible, and immunogenicity is possible as with all therapeutic proteins. Patients are monitored for signs of anaphylaxis and acute allergic reaction, and medical support must be readily available when glucarpidase is given.

• Folinic acid (leucovorin): a competitive substrate of glucarpidase, which can lower folinic acid concentrations and weaken folinic acid rescue unless it is timed as recommended. Folinic acid should not be given within 2 hours before or after glucarpidase.
• Other folate analogues or folate analogue metabolic inhibitors: glucarpidase may reduce their concentrations.
• Methotrexate laboratory assays: immunoassays are unreliable on samples taken after glucarpidase because DAMPA interferes and makes the methotrexate result read too high. A chromatographic (HPLC) method is recommended.

Glucarpidase is intended for use under medical supervision. Local treatment protocols or guidelines should be used, where available, to decide when to give it, so that all methotrexate doses and infusion durations are taken into account.

Dose

• 50 Units/kg as a single dose, by intravenous bolus injection over 5 minutes.
• Once delayed methotrexate elimination or risk of toxicity is established, glucarpidase is given without delay.

When to Give It

• Giving glucarpidase is considered when plasma methotrexate concentrations are more than 2 standard deviations above the mean expected excretion curve. The SmPC tabulates threshold plasma methotrexate concentrations (in µM) at 24, 36, 42 and 48 hours after the start of the infusion for each methotrexate dose and infusion duration; consult it with the local protocol.
• For delayed elimination the optimal window is within 48 to 60 hours of the start of the high-dose methotrexate infusion. Life-threatening toxicity may not be preventable beyond about 60 hours, but clinical data show glucarpidase remains effective later.

Preparation and Giving

• Reconstitute each vial of 1,000 units with 1 mL of sterile 0.9% sodium chloride solution immediately before use; do not dilute further. Each mL then contains 1,000 units.
• Use a syringe suited to small volumes. A full 1 mL may not be withdrawable, but at least 0.90 mL supplies enough for dosing.
• Flush the intravenous line before and after the injection.

Folinic Acid

Folinic acid is not given within 2 hours before or after glucarpidase. It is still needed, no earlier than 2 hours after glucarpidase, to replenish the intracellular folate that methotrexate continues to block.

Special Populations

• Renal impairment: no dose adjustment.
• Children: no dose adjustment for the paediatric population; no data are available below 28 days of age.

Traceability

The trade name and batch number of the administered product should be clearly recorded.

Monitoring Methotrexate After Glucarpidase

• Baseline plasma methotrexate and renal function should be measured and followed throughout high-dose methotrexate therapy.
• DAMPA interferes with immunoassays. It falls with a mean half-life of 8.6 hours and in most patients is below 1 µmol/L within 48 hours; levels above 1 µmol/L were seen beyond 3 days in 3% or fewer of patients, and in about 9% of patients with a baseline methotrexate of 50 µmol/L or more they persisted beyond 4 days.
• Without a specific HPLC assay, the folinic acid dose in the 48 hours after glucarpidase should be based on a methotrexate level taken before glucarpidase. Within 48 hours, immunoassay results should not be relied on to detect rebound, and HPLC confirmation should be considered; after 48 hours immunoassay is reliable in most patients.
• Routine monitoring of methotrexate levels continues according to local guidelines.

Supportive Care Continues

Glucarpidase does not reverse existing renal damage or renal failure caused by methotrexate; it removes methotrexate to lower the risk of further kidney injury. Hydration, urine alkalinisation and other supportive care begin at the start of methotrexate treatment and continue under local guidelines.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data on glucarpidase in pregnancy. Because methotrexate, which is contraindicated in pregnancy and genotoxic and teratogenic, is a prerequisite for glucarpidase, no additional risk is thought to arise. It should be given to a pregnant woman only if clearly needed.
• Breastfeeding: it is unknown whether glucarpidase or its metabolites pass into breast milk; a risk to the infant cannot be excluded, so a decision is made whether to stop breastfeeding or avoid the treatment.
• Fertility: there are no or limited data; animal fertility studies were not performed.

Effect on Driving

Glucarpidase has no or negligible influence on the ability to drive and use machines.

Store vials in a refrigerator at 2–8 °C. Do not freeze. Keep cold-chain handling intact until use. After reconstitution, use immediately: chemical and physical stability was shown for 24 hours at 2–8 °C, but from a microbiological point of view any later use is the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions. Supplied as one 3 mL type 1 glass vial with a bromobutyl stopper and blue flip-off seal per pack.

5 years for unopened vials. After reconstitution, see Storage Conditions.

Prescription only (Rx), on restricted medical prescription (Annex II B). Glucarpidase is given in hospital under medical supervision as an intravenous bolus, so it is supplied to the hospital that administers it, under cold-chain (2–8 °C) conditions.