Glucarpidase

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:

KEGG DRUG: Glucarpidase [Link]

Download FASTA Format

Synonyms

Carboxypeptidase G2
Folate hydrolase G2
Glucarpidase
Glutamate carboxypeptidase
Pteroylmonoglutamic acid hydrolase G2

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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

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

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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 C_max 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
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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.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Voraxaze	Injection, powder, for solution	1000 IU/ml	Intravenous	Serb Sas	2022-05-04	Not applicable
Voraxaze	Injection, powder, for solution	1000 [USP'U]/1	Intravenous	BTG International Inc.	2012-04-01	Not applicable

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
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

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Acute Lymphoblastic Leukemia (ALL)	1
2	Completed	Treatment	Neoplasm	1
2	Recruiting	Treatment	Diffuse Large B-Cell Lymphoma (DLBCL) / Therapeutic Agent Toxicity	1
2	Suspended	Treatment	Lymphoma	1
2	Terminated	Treatment	Osteosarcoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	1000 IU/ml
Injection, powder, for solution	Intravenous	1000 [USP'U]/1
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

Glucarpidase

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties