Glucarpidase
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Identification
- Summary
Glucarpidase is a carboxypeptidase enzyme used to reduce plasma concentrations of methotrexate in patients with impaired renal function.
- Brand Names
- Voraxaze
- Generic Name
- Glucarpidase
- DrugBank Accession Number
- DB08898
- Background
Glucarpidase is a recombinant carboxypeptidase G2 produced by genetically modified Escherichia coli bacteria. It is a 390-amino acid homodimer protein.4 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.1,2
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.3 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.4 Glucarpidase was first approved by the FDA in January 2012,1 followed by the European Commission's approval in January 2022.5 It is marketed as VORAXAZE.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Recombinant Enzymes - Protein Structure
- Protein Chemical Formula
- C3670H5926N10114O1140S12
- Protein Average Weight
- 83000.0 Da
- Sequences
>Sequence MRPSIHRTAIAAVLATAFVAGTALAQKRDNVLFQAATDEQPAVIKTLEKLVNIETGTGDA EGIAAAGNFLEAELKNLGFTVTRSKSAGLVVGDNIVGKIKGRGGKNLLLMSHMDTVYLKG ILAKAPFRVEGDKAYGPGIADDKGGNAVILHTLKLLKEYGVRDYGTITVLFNTDEEKGSF GSRDLIQEEAKLADYVLSFEPTSAGDEKLSLGTSGIAYVQVNITGKASHAGAAPELGVNA LVEASDLVLRTMNIDDKAKNLRFNWTIAKAGNVSNIIPASATLNADVRYARNEDFDAAMK TLEERAQQKKLPEADVKVIVTRGRPAFNAGEGGKKLVDKAVAYYKEAGGTLGVEERTGGG TDAAYAALSGKPVIESLGLPGFGYHSDKAEYVDISAIPRRLYMARRLIMDLGAGK
Download FASTA FormatReferences:
- KEGG DRUG: Glucarpidase [Link]
- Synonyms
- Carboxypeptidase G2
- Folate hydrolase G2
- Glucarpidase
- Glutamate carboxypeptidase
- Pteroylmonoglutamic acid hydrolase G2
Pharmacology
- 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.4 In the European prescribing information, glucarpidase is specified for use in adults and children aged 28 days and older.6
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.4
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prophylaxis of Methotrexate toxicity •••••••••••• ••••••••••• •••••• ••••••• ••••••••• ••••••••• ••••••• •••••••••••• ••••••••• ••••••••• Prophylaxis of Methotrexate toxicity •••••••••••• ••••••• •••••••••••• •••••••••• •••••••• ••••• •••••••• ••••••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
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.4 It reduced the circulating levels of methotrexate in pediatric and adult patients, as well as patients with delayed methotrexate elimination.3
- 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.1
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),4 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.1 Glucarpidase provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.4
- Absorption
In healthy adults who received glucarpidase 50 units/kg, the mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-INF) was 23.3 μg x h/mL.4
- Volume of distribution
In healthy adults who received glucarpidase 50 units/kg, the mean volume of distribution (Vd) was 3.6 L. 4
- Protein binding
There is limited information.
- Metabolism
There is limited information.
- Route of elimination
There is limited information.
- Half-life
Following intravenous administration of glucarpidase 50 units/kg in healthy adults, serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours and serum total glucarpidase concentration declined with a mean elimination half-life of 9 hours. 4
- Clearance
The mean systemic clearance (CL) was 7.5 mL/min in healthy adults who received glucarpidase 50 units/kg.4
- Adverse Effects
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- Toxicity
There is limited information regarding the LD50 and overdose of glucarpidase.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareFolic 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. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Voraxaze Injection, powder, for solution 1000 [USP'U]/1 Intravenous BTG International Inc. 2012-04-01 Not applicable US Voraxaze Injection, powder, for solution 1000 IU/ml Intravenous Serb s.a. 2022-05-04 Not applicable EU
Categories
- ATC Codes
- V03AF09 — Glucarpidase
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2GFP9BJD79
- CAS number
- 9074-87-7
References
- General References
- Green JM: Glucarpidase to combat toxic levels of methotrexate in patients. Ther Clin Risk Manag. 2012;8:403-13. doi: 10.2147/TCRM.S30135. Epub 2012 Nov 22. [Article]
- Tuffaha HW, Al Omar S: Glucarpidase for the treatment of life-threatening methotrexate overdose. Drugs Today (Barc). 2012 Nov;48(11):705-11. doi: 10.1358/dot.2012.48.11.1871575. [Article]
- Schwartz S, Borner K, Muller K, Martus P, Fischer L, Korfel A, Auton T, Thiel E: Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007 Nov;12(11):1299-308. doi: 10.1634/theoncologist.12-11-1299. [Article]
- FDA Approved Drug Products: VORAXAZE (glucarpidase) for injection, for intravenous use [Link]
- GlobeNewswire: SERB receives EU approval for Voraxaze® (glucarpidase) as Rescue Therapy for High Dose Methotrexate Toxicity [Link]
- Summary of Product Characteristics: Voraxaze (glucarpidase) intravenous injection [Link]
- External Links
- UniProt
- P06621
- KEGG Drug
- D10260
- PubChem Substance
- 347910382
- 1242127
- ChEMBL
- CHEMBL1863515
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Glucarpidase
- FDA label
- Download (367 KB)
- MSDS
- Download (83.7 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Approved for Marketing Not Available Neoplasm 1 somestatus stop reason just information to hide Not Available Completed Supportive Care Neurologic toxicity / Unspecified Adult Solid Tumor, Protocol Specific / Unspecified Childhood Solid Tumor, Protocol Specific 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Acute Kidney Injury (AKI) / Therapeutic Agent Toxicity 1 somestatus stop reason just information to hide 3 Completed Treatment Acute Lymphoblastic Leukemia (ALL) 1 somestatus stop reason just information to hide 2 Completed Treatment Neoplasm 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 1000 [USP'U]/1 Injection, powder, for solution Intravenous 1000 IU/ml Powder, for solution Intravenous 1000 IU/ml - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Drug created at June 05, 2013 04:24 / Updated at January 27, 2022 21:15