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
References:
  1. KEGG DRUG: Glucarpidase [Link]
Download FASTA Format
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

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Associated Conditions
Contraindications & Blackbox Warnings
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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.
DrugInteraction
Folic acidThe 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.
LeucovorinThe 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.
LevoleucovorinThe 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 acidThe 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.
MethotrexateThe 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.
PafolacianineThe 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.
PemetrexedThe 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.
PralatrexateThe 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.
RaltitrexedThe 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.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VoraxazeInjection, powder, for solution1000 IU/mlIntravenousSerb Sas2022-05-04Not applicableEU flag
VoraxazeInjection, powder, for solution1000 [USP'U]/1IntravenousBTG International Inc.2012-04-01Not applicableUS flag

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
  1. 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]
  2. 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]
  3. 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]
  4. FDA Approved Drug Products: VORAXAZE (glucarpidase) for injection, for intravenous use [Link]
  5. GlobeNewswire: SERB receives EU approval for Voraxaze® (glucarpidase) as Rescue Therapy for High Dose Methotrexate Toxicity [Link]
  6. Summary of Product Characteristics: Voraxaze (glucarpidase) intravenous injection [Link]
UniProt
P06621
KEGG Drug
D10260
PubChem Substance
347910382
RxNav
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
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Lymphoblastic Leukemia (ALL)1
2CompletedTreatmentNeoplastic Disease1
2RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL) / Therapeutic Agent Toxicity1
2RecruitingTreatmentMalignant Lymphomas1
2TerminatedTreatmentSarcoma, Osteogenic1
2TerminatedTreatmentSarcoma, Osteogenic / Spindle Cell Sarcoma of Bone1
1CompletedTreatmentKidney Diseases1
1CompletedTreatmentLeukemias / Malignant Lymphomas / Sarcoma, Osteogenic1
1Not Yet RecruitingTreatmentPrimary Central Nervous System Lymphoma (PCNSL)1
1, 2CompletedTreatmentChemotherapeutic Agent Toxicity / Malignant Lymphomas / Mucositis / Neurologic toxicity1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous1000 IU/ml
Injection, powder, for solutionIntravenous1000 [USP'U]/1
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