Glucarpidase is the recombinant form of the Pseudomonas sp. (strain RS-16) enzyme carboxypeptidase G2 that is produced in Escherichia coli. In patients, glucarpidase inactivates methotrexate, and other antifolates, by hydrolyzing glutamate on the carboxyl-terminal of these compounds. Therefore since methotrexate is eliminated enzymatically and not by the kidneys, glucarpidase is indicated in patients on methotrexate treatment who have kidney dysfunction, and are experiencing an abnormally high plasma concentration of methotrexate (>1 micromole per liter). Glucarpidase is marketed under the brand name Voraxaze®.
Glucarpidase is a recombinant carboxypeptidase G2 produced by genetically modified Escherichia coli bacteria. It is a 390 amino acid homodimer protein.[rx] High-dose methotrexate, an antifolate agent, has been widely and safely used for many decades in treating various cancers; however, even with aggressive hydration, urine alkalinization, and leucovorin rescue, some patients still develop high-dose methotrexate-induced nephrotoxicity. This can lead to delayed renal clearance of methotrexate and elevated drug plasma levels, increasing the risk of methotrexate toxicity.[rx,rx]
After the discovery of certain bacteria with the capacity to inactivate folate analogs such as methotrexate, carboxypeptidase G was identified and Carboxypeptidase G1 was first isolated from Pseudomonas stutzeri in 1967. In 1983, the gene for carboxypeptidase G2, or glucarpidase, was derived from Pseudomonas sp. strain RS-16 to be cloned into Escherichia coli, allowing the enzyme to be produced in sufficient quantities for therapeutic purposes.[rx] Glucarpidase is an enzyme that can rapidly hydrolyze methotrexate into its nontoxic metabolites. It prevents methotrexate toxicity in patients with renal dysfunction who are undergoing high-dose methotrexate treatment, as it provides an alternative non-renal pathway for methotrexate elimination.[rx] Glucarpidase was first approved by the FDA in January 2012,[rx] followed by the European Commission’s approval in January 2022.[rx] It is marketed as VORAXAZE.
Glucarpidase (Voraxaze) is a medication used for the treatment of elevated levels of methotrexate (defined as 1 micromol/L) during the treatment of cancer patients who have impaired kidney function (and thus cannot reduce the drug to safe levels sufficiently after the drug has been given). Glucarpidase is an enzyme that inactivates methotrexate rapidly after injection. Because this agent reduces systemic levels of methotrexate and could therefore interfere with efficacy, it is not recommended for use in patients with normal or only slightly impaired kidney function or in whom serum levels are normal. The main antidote for methotrexate overdoses prior to the approval of this drug was high doses of folinic acid. However, this agent was not always sufficient at preventing kidney failure due to methotrexate. Glucarpidase also degrades folinic acid so the two should not be used together (within two hours of one another).
Mechanism of action
Methotrexate is an anticancer agent widely used to treat various cancers: it is often used in higher doses in leukemias and lymphomas. As methotrexate and its metabolites are primarily excreted in the kidneys, patients with reduced renal function are at an elevated risk for increased drug exposure and methotrexate toxicity. Methotrexate itself can cause renal toxicity at high doses: methotrexate-induced renal damage can occur by precipitation of methotrexate and its breakdown products in the renal tubules, or from a direct toxic effect of the drug.[rx]
Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites glutamate and 2,4-diamino-N10-methylpteroic acid (DAMPA),[rx] which is a nontoxic metabolite. DAMPA is later excreted in urine or further metabolized by the liver into hydroxyl-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide.[rx] Glucarpidase provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.[rx]
Glucarpidase acts as an antidote to toxic methotrexate levels by eliminating methotrexate by a non-kidney route. In one study, methotrexate concentration measured by a chromatographic method was reduced by more than 97% within 15 minutes in all 22 treatment-evaluable patients who received glucarpidase 50 Units/kg: this effect was maintained at a >95% reduction up to 8 days in 20 of the 22 patients.[rx] It reduced the circulating levels of methotrexate in pediatric and adult patients, as well as patients with delayed methotrexate elimination.[rx]
Indications
- Glucarpidase is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function.[rx] In the European prescribing information, glucarpidase is specified for use in adults and children aged 28 days and older.[rx]
- Glucarpidase is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate.[rx]
- Glucarpidase is a carboxypeptidase enzyme used to reduce plasma concentrations of methotrexate in patients with impaired renal function.
- Treatment of toxic plasma methotrexate concentrations (greater than 1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function.
Use in Cancer
Glucarpidase is approved to treat:
- Toxic blood levels of the anticancer drug methotrexate. Glucarpidase is used to remove methotrexate from the body in adults and children whose kidneys are not working as they should.
Contraindications
- Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specifically for the dose of methotrexate administered) or those with
normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.
Dosage
Strengths: 1000 units
Methotrexate Overdosage
- Single IV injection of 50 Units/kg
Pediatric Dose for Methotrexate Overdosage
- Children 1 month of age or older: Single IV injection of 50 units/kg
Administration advice:
- Administer intravenously as a bolus injection over 5 minutes.
- Flush the intravenous line before and after administration.
Side Effects
The Most Common
- nausea
- vomiting
- fever
- chills
- flushing or feeling hot
- rash
- hives
- itching
- throat tightness or difficulty breathing
- feelings of numbness, tingling, pricking, burning or creeping on the skin
- headache
More Common
- Blurred vision
- confusion
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
- sweating
- unusual tiredness or weakness
- Burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
- feeling of warmth
- nausea
- redness of the face, neck, arms, and occasionally, upper chest
- vomiting
- Diarrhea
- shakiness in the legs, arms, hands, or feet
- sore throat
- trembling or shaking of the hands or feet
Rare
- Cough
- difficulty with swallowing
- dizziness
- fever
- headache
- hives
- hoarseness
- irritation
- itching
- joint pain, stiffness, or swelling
- nervousness
- pounding in the ears
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- rash
- redness of the skin
- shortness of breath
- slow or fast heartbeat
- swelling of the eyelids, face, lips, hands, or feet
- tightness in the chest
- troubled breathing or swallowing
- wheezing
Drug Interactions
| DRUG | INTERACTION |
|---|---|
| Folic acid | The serum concentration of the active metabolites of Folic acid can be reduced when Folic acid is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Leucovorin | The serum concentration of the active metabolites of Leucovorin can be reduced when Leucovorin is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Levoleucovorin | The serum concentration of the active metabolites of Levoleucovorin can be reduced when Levoleucovorin is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Levomefolic acid | The serum concentration of the active metabolites of Levomefolic acid can be reduced when Levomefolic acid is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Methotrexate | The serum concentration of the active metabolites of Methotrexate can be reduced when Methotrexate is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Pafolacianine | The serum concentration of the active metabolites of Pafolacianine can be reduced when Pafolacianine is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Pemetrexed | The serum concentration of the active metabolites of Pemetrexed can be reduced when Pemetrexed is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Pralatrexate | The serum concentration of the active metabolites of Pralatrexate can be reduced when Pralatrexate is used in combination with Glucarpidase resulting in a loss in efficacy. |
| Raltitrexed | The serum concentration of the active metabolites of Raltitrexed can be reduced when Raltitrexed is used in combination with Glucarpidase resulting in a loss in efficacy. |
Pregnancy and Lactation
US FDA pregnancy category Not Assigned
Pregnancy
The manufacturer makes no recommendation regarding use during pregnancy. There is no data on use in pregnant women or animal studies to know the risks of this drug, including the risk of fetal harm, major birth defects, miscarriage, or adverse maternal or fetal effects. This drug is administered in combination with methotrexate which may cause embryo-fetal harm; the methotrexate manufacturer product information should be consulted.
Lactation
The manufacturer makes no recommendation regarding use during lactation. There is no information regarding this drug on its presence in human milk, its effects on a breastfed infant, or its effects on milk production. This drug is administered in combination with methotrexate; the methotrexate manufacturer’s product information should be consulted.
How should this medicine be used?
Glucarpidase comes as a powder to be mixed with liquid and injected intravenously (into a vein). It is usually given over 5 minutes as a one-time dose. Glucarpidase is given along with leucovorin (another medication used to prevent the harmful effects of methotrexate) until laboratory tests show treatment is no longer needed.
What special precautions should I follow?
Before taking glucarpidase,
- tell your doctor and pharmacist if you are allergic to glucarpidase, any other medications, or any of the ingredients in glucarpidase injection. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: folic acid (Folicet, in multivitamins); levoleucovorin (Fusilev); or pemetrexed (Alimta). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- if you are receiving leucovorin, it should be given at least 2 hours before or 2 hours after glucarpidase.
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding . If you become pregnant while taking glucarpidase, call your doctor.
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125327lbl.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125327s064lbl.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125327Orig1s000TOC.cfm
- https://go.drugbank.com/drugs/DB08898
- https://www.drugs.com/mtm/glucarpidase.html
- https://pubchem.ncbi.nlm.nih.gov/compound/Glucarpidase
- https://www.mayoclinic.org/drugs-supplements/glucarpidase-intravenous-route/side-effects/drg-20075448
- https://medlineplus.gov/druginfo/meds/a613009.html
- https://en.wikipedia.org/wiki/Glucarpidase
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Glucarpidase
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glucarpidase (P/0176/2013)Voraxaze (EMEA/H/C/005467)
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ATC Code
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glucarpidase
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Glucarpidase
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PubChem
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glucarpidase
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GHS Classification Tree
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