Overview
Glucarpidase is a recombinant carboxypeptidase G2 produced by genetically modified Escherichia coli bacteria. It is a 390-amino acid homodimer protein. 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. 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. 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. Glucarpidase was first approved by the FDA in January 2012, followed by the European Commission's approval in January 2022. It is marketed as VORAXAZE.
Indication
Glucarpidase is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per litre) 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. In the European prescribing information, glucarpidase is specified for use in adults and children aged 28 days and older. 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.
Associated Conditions
- Methotrexate toxicity
Research Report
Glucarpidase (Voraxaze®): A Comprehensive Pharmacological and Clinical Monograph
Section 1: Introduction and Executive Summary
1.1. Overview
Glucarpidase, marketed under the trade name Voraxaze®, is a high-impact, specific-use biotechnology product that functions as a critical rescue agent in oncologic supportive care. It is a recombinant carboxypeptidase G2 enzyme, specifically engineered to provide a rapid, non-renal pathway for the elimination of the chemotherapeutic agent methotrexate.[1] Its indication is narrowly defined for the treatment of patients who develop toxic plasma concentrations of methotrexate following high-dose therapy, a life-threatening complication precipitated by acute kidney injury (AKI).[4] By enzymatically degrading circulating methotrexate into inactive metabolites, glucarpidase offers a definitive and immediate intervention that is independent of the patient's compromised renal function, representing a significant advancement in managing iatrogenic drug toxicity.
1.2. The Clinical Problem: High-Dose Methotrexate Toxicity
High-dose methotrexate (HDMTX), defined as doses exceeding 500 mg/m², is a cornerstone of curative-intent chemotherapy regimens for various malignancies, including osteosarcoma, acute lymphoblastic leukemia (ALL), and certain lymphomas.[3] The therapeutic efficacy of methotrexate stems from its action as an antifolate, inhibiting the enzyme dihydrofolate reductase (DHFR) and thereby disrupting the synthesis of purines and thymidylate essential for DNA replication in rapidly dividing cancer cells.[7]
Clinical Trials
Title | Posted | Study ID | Phase | Status | Sponsor |
|---|---|---|---|---|---|
2023/06/12 | N/A | Recruiting | |||
2024/10/29 | Phase 1 | Recruiting | |||
2021/08/26 | Phase 2 | Terminated | Fundacion CRIS de Investigación para Vencer el Cáncer | ||
2021/04/12 | Phase 1 | Completed | |||
2020/12/16 | Phase 2 | Suspended | |||
2019/05/22 | Early Phase 1 | Active, not recruiting | |||
2018/09/26 | Early Phase 1 | Recruiting | |||
2013/12/27 | Phase 2 | Terminated | |||
2011/03/01 | Phase 3 | Completed | Nordic Society for Pediatric Hematology and Oncology | ||
2008/08/04 | Phase 1 | Completed |
FDA Drug Approvals
Approved Product | Manufacturer | NDC Code | Route | Strength | Effective Date |
|---|---|---|---|---|---|
| BTG International Inc. | 50633-210 | INTRAVENOUS | 1000 [USP'U] in 1 1 | 10/24/2018 |
EMA Drug Approvals
Approved Product | Authorization Holder | Status | Issued Date |
|---|---|---|---|
Authorised | 1/11/2022 |
HSA Drug Approvals
Approved Product | Manufacturer | Approval Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No HSA approvals found for this drug. | |||||
NMPA Drug Approvals
Approved Product | Company | Approval Number | Drug Type | Dosage Form | Approval Date |
|---|---|---|---|---|---|
| No NMPA approvals found for this drug. | |||||
PPB Drug Approvals
Approved Product | Registration No. | Company | Licence No. | Strength | Registration Date |
|---|---|---|---|---|---|
| No PPB approvals found for this drug. | |||||
TGA Drug Approvals
Approved Product | ARTG ID | Sponsor | Registration Type | Status | Registration Date |
|---|---|---|---|---|---|
| No TGA approvals found for this drug. | |||||
Health Canada Drug Approvals
Approved Product | Company | DIN | Dosage Form | Strength | Market Date |
|---|---|---|---|---|---|
| No Health Canada approvals found for this drug. | |||||
CIMA AEMPS Drug Approvals
Approved Product | Company | Registration Number | Pharmaceutical Form | Prescription Type | Status |
|---|---|---|---|---|---|
| No CIMA AEMPS (Spain) approvals found for this drug. | |||||
Philippines FDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Philippines FDA approvals found for this drug. | |||||
Saudi SFDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Saudi SFDA approvals found for this drug. | |||||
Malaysia NPRA Drug Approvals
Approved Product | Company | Registration Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Malaysia NPRA approvals found for this drug. | |||||
UK EMC Drug Information
Medicine Name | MA Holder | MA Number | Pharmaceutical Form | Active Ingredient | Authorization Date |
|---|---|---|---|---|---|
| No UK EMC drug information found for this drug. | |||||
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