Asparaginase Erwinia chrysanthemi

Identification

Summary

Asparaginase Erwinia chrysanthemi is an asparagine-specific enzyme used as part of a chemotherapeutic regimen to treat patients with acute lymphoblastic leukemia and lymphoblastic lymphoma.

Brand Names
Erwinaze
Generic Name
Asparaginase Erwinia chrysanthemi
DrugBank Accession Number
DB08886
Background

Asparaginase Erwinia chrysanthemi is an asparaginase-specific enzyme derived from Erwinia chrysanthemi used as an anticancer agent. It works by depleting the stores of an important amino acid called asparagine, which is involved in DNA synthesis and cell survival of malignant cells, leading to cell death.5 L-asparaginase was first identified in 1963,2 and there are different formulations of L-asparaginase, including Asparaginase Escherichia coli and a pegylated form of this enzyme, Pegaspargase.1 Asparaginase Erwinia chrysanthemi and Asparaginase Escherichia coli differ in their pharmacokinetic and immunogenic profiles;6 thus, those who are allergic to Asparaginase Escherichia coli do not cross-react to Asparaginase Erwinia chrysanthemi.2 Studies show that substitution of Erwinia asparaginase for E. coli-derived asparaginase following an allergic reaction has been safe and effective.3

Asparaginase Erwinia chrysanthemi was first approved by the FDA in November 2011 to treat patients with acute lymphoblastic leukemia (ALL) who are allergic to E. coli-derived asparaginase: it has been used as part of multi-agent chemotherapy.4 In June 2021, the recombinant form of asparaginase Erwinia chrysanthemi was approved by the FDA as a component of a chemotherapy regimen to treat acute lymphoblastic leukemia and lymphoblastic lymphoma in adult and pediatric patients who are allergic to the E. coli-derived asparaginase.7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Db08886
Protein Chemical Formula
C1546H2510N432O476S9
Protein Average Weight
140000.0 Da
Sequences
>Protein sequence for asparaginase (Erwinia chrysanthemi) monomer
ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM
ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA
MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN
EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH
GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP
AHARILLMLALTRTSDPKVIQEYFHTY
References:
  1. Therapeutic Targets Database: TTD Biologic drug sequences in fasta format [Link]
Download FASTA Format
Synonyms
  • Asparaginase (Erwinia chrysanthemi)
  • Asparaginase (Erwinia)
  • Asparaginase Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi (recombinant)
  • asparaginase erwinia chrysanthemi (recombinant)-rywn
  • Crisantaspase
  • Erwinase
  • Erwinaze
  • Erwinia asparaginase
  • Erwinia chrysanthemi
  • Erwinia L-asparaginase
  • L-asparaginase (Erwinia)
  • L-asparaginase, Erwinia chrysanthemi
External IDs
  • JZP-458

Pharmacology

Indication

Asparaginase Erwinia chrysanthemi is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma in adults and children who have developed hypersensitivity to E. coli-derived asparaginase.4,8

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Asparaginase Erwinia chrysanthemi is an enzyme that exerts cytotoxic effects on leukemic cells by depleting the source of an amino acid asparagine, which plays a role in the proliferation, protein metabolism, and survival of malignant cells.4

Mechanism of action

Asparaginase Erwinia chrysanthemi is a tetrameric enzyme made up of four identical subunits, each having a molecular weight of about 35 kDa. It rapidly and completely catalyzes the deamidation reaction of L-asparagine to aspartic acid and ammonia, resulting in reduced levels of circulating asparagine in the plasma. Asparagine is essential for DNA synthesis, RNA synthesis, protein metabolism, and survival of leukemic cells 3; however, they lack the asparagine synthetase enzyme and depend on an exogenous source of asparagine. Asparaginase Erwinia chrysanthemi depletes the source of asparagine for leukemic cells, resulting in the death of leukemic cells.4,8 In addition to asparagine, asparaginase Erwinia chrysanthemi also deaminates glutamine to a lesser extent.1

Absorption

In patients two to 80 years of age, intramuscular administration of asparaginase Erwinia chrysanthemi 25,000 International Units (IU)/m2 resulted in serum trough asparaginase concentrations ≥ 0.1 IU/mL at either 48-hour (n=35) or 72-hour (n=13) post third dose. 80% of patients evaluted at 48 hours and 38% of patients evaluated at 72 hours had serum asparaginase activity levels > 0.4 IU/mL.4 For asparaginase Erwinia chrysanthemi (recombinant)-rywn, the median tmax is 10 hours and the mean absolute bioavailability is 37% in healthy subjects.8

Volume of distribution

The volume of distribution of asparaginase Erwinia chrysanthemi can be up to 5 L/m2.5 The geometric mean (%CV) apparent volume of distribution of asparaginase Erwinia chrysanthemi (recombinant)-rywn was 1.48 L/m2 (49%).8 While asparaginases are not detectable in cerebrospinal fluid, asparagine in cerebrospinal fluid is depleted with systemic administration of any formulation of asparaginases.5

Protein binding

There is limited information on protein binding.

Metabolism

Metabolism of asparaginase Erwinia chrysanthemi has not been fully characterized; however, it is suspected to be metabolized into small peptides by catabolic pathways.8

Route of elimination

Trace amounts of asparaginases are found in urine.8

Half-life

The apparent half-life (%CV) of asparaginase Erwinia chrysanthemi (recombinant)-rywn is 18.2 hours (16%).8 Asparaginase Erwinia chrysanthemi has a shorter half-life compared with the E. coli-derived preparations.1

Clearance

The geometric mean (%CV) apparent clearance of asparaginase Erwinia chrysanthemi (recombinant)-rywn is 0.31 L/hour/m2 (36%).8

Adverse Effects
Adverseeffects
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Toxicity

There are no known cases of overdose with asparaginase Erwinia chrysanthemi.4 In clinical trials, the most common adverse effects were hypersensitivity reactions, pancreatic toxicity, blood clots, hemorrhage, and liver toxicity.7 Pancreatitis occurs in 8-14% of pediatric patients, with adolescents at the highest risk for developing this adverse event. Pancreatitis typically occurs after the first few weeks of asparaginase administration, which suggests this complication occurs from an underlying predisposition rather than a cumulative drug effect.1

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
AllantoinThe therapeutic efficacy of Allantoin can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
CarbamazepineThe therapeutic efficacy of Carbamazepine can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
DantroleneThe therapeutic efficacy of Dantrolene can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Asparaginase Erwinia chrysanthemi.
DexamethasoneThe serum concentration of Dexamethasone can be increased when it is combined with Asparaginase Erwinia chrysanthemi.
EnzalutamideThe therapeutic efficacy of Enzalutamide can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Asparaginase Erwinia chrysanthemi.
EthotoinThe therapeutic efficacy of Ethotoin can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
FosphenytoinThe therapeutic efficacy of Fosphenytoin can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
FurosemideThe therapeutic efficacy of Furosemide can be increased when used in combination with Asparaginase Erwinia chrysanthemi.
Interactions
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Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
Asparaginase Escherichia coliunknownG4FQ3CKY5R9015-68-3Not applicable
International/Other Brands
Rylaze (Jazz Pharmaceuticals plc)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ErwinasePowder, for solution10000 unitIntramuscular; Intravenous; SubcutaneousJazz Pharmaceuticals France Sas2009-07-012021-04-09Canada flag
ErwinaseInjection, powder, lyophilized, for solution10000 [iU]/1mLIntramuscular; IntravenousPorton Biopharma Limited2021-06-01Not applicableUS flag
ErwinazeInjection, powder, lyophilized, for solution10000 [iU]/1mLIntramuscular; IntravenousJazz Pharmaceuticals, Inc.2011-11-182021-07-23US flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ErwinaseAsparaginase Erwinia chrysanthemi (10000 [iU]/1mL)Injection, powder, lyophilized, for solutionIntramuscular; IntravenousPorton Biopharma Limited2021-06-01Not applicableUS flag

Categories

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
D733ET3F9O
CAS number
1349719-22-7

References

General References
  1. Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A, Goekbuget N, Schrappe M, Pui CH: L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011 Jan 15;117(2):238-49. doi: 10.1002/cncr.25489. Epub 2010 Sep 7. [Article]
  2. Salzer WL, Asselin BL, Plourde PV, Corn T, Hunger SP: Development of asparaginase Erwinia chrysanthemi for the treatment of acute lymphoblastic leukemia. Ann N Y Acad Sci. 2014 Nov;1329:81-92. doi: 10.1111/nyas.12496. Epub 2014 Aug 5. [Article]
  3. Egler RA, Ahuja SP, Matloub Y: L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016 Apr-Jun;7(2):62-71. doi: 10.4103/0976-500X.184769. [Article]
  4. FDA Approved Drug Products: ERWINAZE (asparaginase Erwinia chrysanthemi) for injection, intramuscular use [Link]
  5. BC Cancer Asparaginase Monograph [Link]
  6. Pegylated l-asparaginase: Protein Sequence of Erwinia Asparaginase [Link]
  7. FDA Press Announcements: FDA Approves Component of Treatment Regimen for Most Common Childhood Cancer [Link]
  8. FDA Approved Drug Products: RYLAZE (asparaginase erwinia chrysanthemi (recombinant)­ rywn) injection, for intramuscular use [Link]
UniProt
P06608
Genbank
X12746
KEGG Drug
D02997
PubChem Substance
347910380
RxNav
1431738
ChEMBL
CHEMBL1863514
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Asparaginase
FDA label
Download (250 KB)
MSDS
Download (90.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL)2
3CompletedTreatmentAcute Lymphoblastic Leukemia (ALL)2
3RecruitingTreatmentAcute Myeloid Leukemia (AML)1
3RecruitingTreatmentAcute Myeloid Leukemia (AML) / Down Syndrome (DS) / Myelodysplastic Syndromes (MDS) / Myeloid Leukemia Associated With Down Syndrome / Myeloproliferative Neoplasms (MPNs)1
3RecruitingTreatmentB Acute Lymphoblastic Leukemia / B Lymphoblastic Lymphoma / Down Syndrome (DS)1
3RecruitingTreatmentLeukemia, Lymphoblastic, Acute, Pediatric2
2Active Not RecruitingTreatmentLymphoma, Lymphoblastic1
2CompletedTreatmentAcute Lymphoblastic Leukemia (ALL) / Lymphoma, Lymphoblastic2
2CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
2RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL) / Acute Myeloid Leukemia (AML)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionIntramuscular; Intravenous; Subcutaneous10000 unit
Injection, powder, lyophilized, for solutionIntramuscular; Intravenous10000 [iU]/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Drug created on May 27, 2013 23:48 / Updated on September 19, 2021 19:53