Asparaginase Erwinia chrysanthemi

Identification

Name
Asparaginase Erwinia chrysanthemi
Accession Number
DB08886
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Erwinaze (asparaginase Erwinia chrysanthemi) contains an asparaginase specific enzyme derived from Erwinia chrysanthemi [4]. Specifically, this L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa [4]. The activity of Erwinaze is expressed in terms of International Units. It is an antineoplastic agent and was FDA approved in November 19, 2011 [4].

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
Download FASTA Format
Synonyms
  • Asparaginase (Erwinia)
  • Asparaginase Erwinia chrysanthemi
  • Crisantaspase
  • Erwinia asparaginase
  • Erwinia chrysanthemi
  • L-asparaginase (Erwinia)
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ErwinasePowder, for solution10000 unitIntramuscular; Intravenous; SubcutaneousJazz Pharmaceuticals France Sas2009-07-01Not applicableCanada
ErwinazeInjection, powder, lyophilized, for solution10000 [iU]/mLIntramuscular; IntravenousJazz Pharmaceuticals2011-11-18Not applicableUs
Categories
UNII
D733ET3F9O
CAS number
1349719-22-7

Pharmacology

Indication

Asparaginase Erwinia chrysanthemi is for the treatment of patients with acute lymphoblastic leukemia (ALL) that have developed a hypersensitivity to E. coli-derivied asparaginase [4]. It is a component of a multi-agent chemotherpeutic regimen [4] for the treatment of the aforementioned disease and is considered second- or third- line treatment in European and American protocols [1].

Associated Conditions
Pharmacodynamics

Asparagine is ordinarily found incorporated into most endogenous proteins [6]. In its absence however, protein synthesis is halted - which in turn also results in the inhibition of the RNA and DNA synthesis necessary for cellular proliferation [6].

One commonality between Acute Lymphoblastic Leukaemia (ALL), Acute Myeloid Leukaemia (AML), and Non-Hodgkin's Lymphoma (especially the lymphoblastic form) is the absence of asparagine synthetase activity in the neoplastic cells associated with these conditions [6]. These neoplastic cells are subsequently dependent upon exogenous asparagine for their proliferation [6].

The anti-neoplastic function of L-asparaginase is consequently a result of the sustained depletion of exogenous asparagine [6]. In particular, Erwinia L-asparaginase catalyses the deamination of asparagine to aspartic acid and the release of an ammonia molecule [6].

In addition, asparaginase also demonstrates a significant glutaminase activity in which it is capable of catalyzing the deamination of glutamine to glutamate and the release of an ammonia molecule [6]. Since glutamine may lead to alternative asparagine synthesis, the ability for asparaginase to facilitate glutamine depletion may complement asparagine depletion [6]. The exact potential to such glutaminase activity, however, remains unknown [6].

Mechanism of action

Asparaginase Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of exogenous asparagine in the plasma [4]. The mechanism of action of Erwinia asparaginase is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine for their protein metabolism and survival [4].

Absorption

The absorption of Erwinia asparaginase is predominantly via denaturation followed by peptidase digestion within GI tract [7].

Volume of distribution

The volume of distribution for Erwinia asparaginase is 5 L/m2 [7]. The partitioning of Erwinia L-asparaginase between lymph and blood shows that this enzyme, in contrast to the E. coli derivative, does not penetrate the capillary endothelium well because negligible amounts are found in the lymph [Label]. Ultimately, although L-asparaginase is capable of penetrating through to the cerebrospinal fluid to a small degree [6] and is also found in limited quantities in lymph [6], the drug subsequently seems to confine itself mainly to the blood compartment of man [Label].

Protein binding

No specific information regarding protein binding has been developed at the moment [7]. Nevertheless, with repeated use Erwinia asparaginase may be bound by specific antibodies and eliminated [6].

Metabolism

At the moment, conclusive data regarding the metabolism and elimination of asparaginase has not yet been developed [7, 3]

Route of elimination

Formally conclusive findings regarding the elimination of Erwinia asparaginase have unfortunately not yet been established. However, some studies posit that the drug may possibly be eliminated using the reticuloendothelial system [7].

Half life

The elimination half-life of Erwinia asparaginase administered via i.m. injection is 16 hours and follows first-order kinetics [Label]. Compared to E.coli-asparaginase, it has a lower half-life [Label] so higher and more frequent doses are necessary. Similarly, the half-life of Erwinia asparaginase after i.v. infusion is approximately 6.4 +/- 0.5 hours [6] and also follows first-order kinetics [Label].

Clearance

The clearance of Erwinia asparaginase is given as 3.4 mL/min/m2 [7].

Toxicity

Erwinia asparaginase is contraindicated in individuals who: (a) have a history of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis, (b) have a history of serious pancreatitis with prior L-asparaginase therapy, (c) have a history of serious thrombosis with prior L-asparaginase therapy, and (d) have a history of serious hemorrhagic events with prior L-asparaginase therapy. [4]

5% of patients in clinical trials have experienced grade 3 and 4 hypersensitivity reactions after being administered Erwinia asparaginase [4].

4% of patients in clinical trials have experienced pancreatitis after using Erwinia asparaginase, where severe pancreatitis serves as a contraindication for continued use of Erwinia asparaginase [4].

5% of patients in clinical trials using Erwinia asparaginase reported experiencing glucose intolerance that was in some cases irreversible [4].

Serious thrombotic events like sagittal sinus thrombosis and pulmonary embolism have been reported with Erwinia asparaginase therapy [4]. After a 2 week course of Erwinia asparaginase therapy by i.m. administration, a majority of patients demonstrated decreased fibrinogen, protein C activity, and anti-thrombin III [4].

The most common adverse reactions (incidence of 1% or greater) associated with Erwinia asparaginase treatment include systemic hypersensitivity, hyperglycemia, abnormal transaminase levels, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain or discomfort, and diarrhea [4].

Patients using Erwinia asparaginase may develop anti-drug antibodies to the medicine after repeated use [4, 6]. The presence of antibodies specific to Erwinia asparaginase is linked with a higher probability of hypersensitivity reactions in patients who are administered Erwinia asparaginase via i.v. infusion compared to i.m. administration [4].

There are no adequate studies of Erwinia asparaginase use in pregnant women [4]. This medication belongs in pregnancy category C and Erwinia asparaginase should only be used during pregnancy if the potential benefits justifies the potential risk to the fetus [4].

It is not known whether Erwinia asparaginase is secreted in human milk, but the potential for serious adverse reactions in nursing infants from Erwinia asparaginase means a decision must be made whether to discontinue nursing or to discontinue Erwinia asparaginase therapy, taking into account the importance of this drug therapy to the mother [4].

Clinical studies have administered Erwinia asparaginase to patients from ages 1 to 18 [4].

The safety and efficacy of Erwinia asparaginase has not been studied in geriatric patients [4].

No long-term carcinogenicity studies in animals have been performed with Erwinia asparaginase [4]. No studies that assess the mutagenic potential of Erwinia asparaginase have been performed either [4].

Fertility and early embryonic development studies in rats demonstrate asparaginase Erwinia chrysanthemi has no effect on male or female fertility when administered i.m. at doses of up to 2000 IU/kg (about 50% of the recommended human dose, after adjustment for total body surface area) every other day for a total of 35 doses [4]. Data for males included decreased sperm count at doses in excess of 500 IU/kg (approximately 12% of the recommended human dose) [4].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Asparaginase Erwinia chrysanthemi.Approved, Investigational, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Asparaginase Erwinia chrysanthemi.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved
DexamethasoneThe serum concentration of Dexamethasone can be increased when it is combined with Asparaginase Erwinia chrysanthemi.Approved, Investigational, Vet Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Asparaginase Erwinia chrysanthemi.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Asparaginase Erwinia chrysanthemi.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Asparaginase Erwinia chrysanthemi.Approved, Investigational
Food Interactions
Not Available

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. [PubMed:20824725]
  2. Yang L, Panetta JC, Cai X, Yang W, Pei D, Cheng C, Kornegay N, Pui CH, Relling MV: Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol. 2008 Apr 20;26(12):1932-9. doi: 10.1200/JCO.2007.13.8404. [PubMed:18421047]
  3. Pinheiro JP, Boos J: The best way to use asparaginase in childhood acute lymphatic leukaemia--still to be defined? Br J Haematol. 2004 Apr;125(2):117-27. doi: 10.1111/j.1365-2141.2004.04863.x. [PubMed:15059133]
  4. Link [Link]
  5. Link [Link]
  6. Electronic Medicines Compendium ERWINASE (Erwinia L-asparaginase), 10000 Units/vial, Lyophilisate for Solution for Injection Monograph [Link]
  7. BC Cancer Asparaginase Monograph [Link]
  8. Pegylated l-asparaginase: Protein Sequence of Erwinia Asparaginase [Link]
  9. Genbank Accession No. CAA32884: L-asparaginase [Dickeya chrysanthemi] [Link]
External Links
UniProt
P06608
Genbank
X12746
KEGG Drug
D02997
PubChem Substance
347910380
ChEMBL
CHEMBL1863514
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Asparaginase
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (250 KB)
MSDS
Download (90.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Lymphoma, Lymphoblastic1
2RecruitingTreatmentALL (Acute Lymphoblastic Leukemia) / B-cell Acute Lymphoblastic Leukemia1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndromes1
2WithdrawnTreatmentAcute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL)1
2, 3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Lymphoblastic Lymphoma1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3RecruitingTreatmentAcute Lymphoblastic Leukemia, Pediatric1
3RecruitingTreatmentChildhood Acute Myeloid Leukemia / Childhood Myelodysplastic Syndrome / Cytopenias / Down Syndrome (DS) / Myeloid Leukemia Associated With Down Syndrome / Myeloproliferative Neoplasms1

Pharmacoeconomics

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

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

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

Drug created on May 27, 2013 17:48 / Updated on July 16, 2018 21:25