What is Glucarpidase?

Here’s a Glucarpidase overview it is a life-saving drug used primarily to treat toxic levels of methotrexate, a chemotherapy drug, in the bloodstream. Methotrexate is often used to treat cancers like leukemia and lymphomas, but high levels of this drug can be dangerous, particularly for patients with kidney problems, as their bodies can’t effectively remove it. Glucarpidase helps these patients by breaking down methotrexate into inactive forms that are easier to eliminate, preventing harmful buildup.

Brand Name	Drug Class	Generic Name
Voraxaze	Enzyme             (Carboxypeptidase)	Glucarpidase

Chemical composition of Glucarpidase:

Glucarpidase is a recombinant enzyme that breaks down methotrexate in the bloodstream. Its chemical composition can be described based on its protein structure:

• Chemical Name: Carboxypeptidase G2 (Glucarpidase)
• Molecular Formula: C1527H2381N421O447S9
• Molecular Weight: Approximately 83,000 Daltons (Da)

Glucarpidase is made up of amino acids that form a protein enzyme. Its structure allows it to cleave the terminal glutamate residues from methotrexate, thereby inactivating the drug and facilitating its removal from the body.

Glucarpidase is produced via recombinant DNA technology using Escherichia coli (E. coli) bacteria, which are genetically engineered to express the enzyme. The final product is a purified protein used for intravenous administration.

FDA Approval: History and Status

The U.S. Food and Drug Administration (FDA) approved glucarpidase under the brand name Voraxaze in January 2012. The drug was fast-tracked due to its ability to address a life-threatening situation (methotrexate toxicity). Before its approval, doctors had few effective options to deal with dangerously high methotrexate levels, especially in patients with impaired kidney function.

• Pre-approval Research: Clinical trials demonstrated that rapid enzyme-based clearance of methotrexate could prevent critical side effects like liver failure, lung damage, and even death.
• Ongoing Status: Glucarpidase remains an important treatment option in cancer therapy support and continues to be used in hospitals and oncology centers worldwide. It is an essential drug for patients who experience delayed methotrexate clearance due to kidney problems.

Mechanism of Action:

How Glucarpidase Works?

Glucarpidase works by acting as an enzyme that breaks down methotrexate. Methotrexate is cleared from the body through the kidneys, but when they are not functioning well, the drug can accumulate to toxic levels. This is where glucarpidase steps in. The enzyme rapidly converts methotrexate into inactive metabolites like DAMPA and glutamate, which are easily excreted from the body through the liver.

• Key Process: Glucarpidase breaks the bond between methotrexate’s glutamate group, which inactivates the drug and enables faster elimination.
• Effectiveness: Glucarpidase can reduce methotrexate levels by up to 97% within 15 minutes of administration, which is critical for patients at risk of serious side effects.

Pharmacokinetics of Glucarpidase: 

Absorption:

• Glucarpidase is given via IV, so absorption is immediate and direct into the bloodstream.

Distribution:

• The enzyme primarily acts in the plasma, where it converts methotrexate into inactive metabolites.
• It has limited distribution outside the bloodstream, and its action is largely confined to the vascular system.

Metabolism:

• Glucarpidase itself is not metabolized by the liver or kidneys; instead, it degrades methotrexate into DAMPA and glutamate, which are more easily eliminated from the body.

Elimination:

• The inactive metabolites, DAMPA and glutamate, are cleared through both renal and non-renal pathways, making the drug highly effective even in patients with kidney impairment.

The half-life of glucarpidase is approximately 5 to 8 hours, but its effects on methotrexate levels are rapid and long-lasting.

Uses of Glucarpidase

The primary use of glucarpidase is in the treatment of severe methotrexate toxicity. Methotrexate is commonly used to treat cancers like leukemia, lymphoma, and osteosarcoma. When patients develop toxicity, especially due to kidney dysfunction, glucarpidase quickly reduces methotrexate levels in the blood, preventing further damage.

Side Effects of Glucarpidase

While glucarpidase is well-tolerated, it can cause both common and serious side effects:

• Common Side Effects: Headache, flushing, nausea, and low blood pressure.
• Serious Side Effects: Severe allergic reactions (e.g., anaphylaxis), significant drops in blood pressure, and seizures in rare cases.

Drug Interactions of Glucarpidase :

Glucarpidase has specific drug interactions that are critical to its effectiveness:

• Methotrexate: Glucarpidase inactivates methotrexate. Care should be taken not to administer leucovorin within 2 hours of glucarpidase, as it can reduce the drug’s efficacy.
• NSAIDs, PPIs, Penicillin: These drugs can reduce methotrexate clearance, increasing the risk of toxicity and should be used cautiously.

Contraindications And Warnings About Glucarpidase:

Glucarpidase should not be used in patients with a known allergy to the drug or any of its components. Special precautions should be taken for patients with liver dysfunction or folate deficiency, as glucarpidase can exacerbate these conditions.

Administration and Dosage of Glucarpidase :

Glucarpidase is administered as a single intravenous (IV) infusion. The standard dose is 50 units per kilogram of body weight, given over 5 minutes. In some cases, a second dose may be necessary based on methotrexate levels.

Access and Cost Considerations

Glucarpidase is a high-cost drug, often covered by insurance for approved uses like methotrexate toxicity. It is only available under the brand name Voraxaze, with no generic alternatives currently on the market. Availability may be limited to hospitals and specialty pharmacies.

Glucarpidase is a critical treatment for methotrexate toxicity, offering life-saving benefits for cancer patients with kidney impairment. Its specialized use, potential side effects, drug interactions, and high cost make it essential for healthcare providers to carefully monitor patients and plan treatment strategies.

FREQUENTLY ASKED QUESTIONS (FAQ’s)

1. What is Glucarpidase used for?

Glucarpidase is primarily used to treat methotrexate toxicity in patients undergoing high-dose chemotherapy, especially those with impaired kidney function.

2. How does Glucarpidase work?

Glucarpidase breaks down methotrexate into inactive compounds, helping the body eliminate it faster and reducing toxic effects in patients with kidney impairment.

3. What are the common side effects of Glucarpidase?

Common side effects include headache, nausea, vomiting, low blood pressure, and allergic reactions.

4. How is Glucarpidase administered?

Glucarpidase is administered via intravenous (IV) infusion in a clinical setting, usually over 5 minutes.

5. What should I avoid when taking Glucarpidase?

Avoid taking leucovorin within 2 hours before or after Glucarpidase, as it may reduce the effectiveness of both drugs.

6. What are the drug interactions of Glucarpidase?

Glucarpidase can interact with methotrexate, leucovorin, NSAIDs, PPIs, and penicillin, affecting the drug’s efficacy and methotrexate clearance.

7. Who should not take Glucarpidase?

People with a known allergy to Glucarpidase or its components should avoid it. Patients with folate deficiency or certain liver conditions should also use it with caution

8. How quickly does Glucarpidase reduce methotrexate levels?

Glucarpidase can reduce plasma methotrexate levels by up to 97% within 15 minutes of administration.

9. Is Glucarpidase available as a generic drug?

No, Glucarpidase is only available under the brand name Voraxaze. There are currently no generic alternatives.

10. What precautions should be taken when using Glucarpidase?

Patients should be monitored for allergic reactions, low blood pressure, and interactions with other medications like leucovorin.

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