Pegaspargase

Identification

Summary

Pegaspargase is a modified form of L-asparagine amidohydrolase used to treat acute lymphoblastic leukemia, which is dependent on an external source of asparagine.

Brand Names
Oncaspar
Generic Name
Pegaspargase
DrugBank Accession Number
DB00059
Background

Pegaspargase is a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase (L-asparagine amidohydrolase), an asparagine-specific enzyme that converts L-asparagine into aspartic acid and ammonia.5 Asparagine is an amino acid that is vital for cell survival. In humans, most normal tissues can produce asparagine through the action of asparagine synthetase. However, leukemia cells have low levels of this enzyme and depend on exogenous sources. Therefore, the use of pegaspargase results in leukemic cell death.1,2,5

Pegaspargase has the same mechanism of action as L-asparaginase derived from Escherichia coli, a previously developed enzyme used for the treatment of acute lymphoblastic leukemia (ALL). However, using L-asparaginase derived from Escherichia coli may cause hypersensitivity in some patients and require frequent administration. The pegylation of pegaspargase allows access to the enzyme's active sites while limiting reticuloendothelial system uptake and reducing immune detection, and it also increases the half-life of L-asparaginase.2,3 In February 1994, pegaspargase was approved by the FDA for the treatment of ALL in patients with hypersensitivity to native forms of L-asparaginase.4

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Protein Chemical Formula
C1377H2208N382O442S17
Protein Average Weight
31731.9 Da
Sequences
>DB00059 sequence
MEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVENLVNA
VPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMEETAYF
LDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVMNDTVLDGR
DVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPKVGIVY
NYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSRVPTGAT
TQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY
Download FASTA Format
Synonyms
  • Peg-asparaginase
  • Peg/L-asparaginase
  • Pegaspargasa
  • Pegaspargase

Pharmacology

Indication

Pegaspargase is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with 1) first-line acute lymphoblastic leukemia or 2) acute lymphoblastic leukemia and hypersensitivity to asparaginase.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatAcute lymphoblastic leukemia•••••••••••••••••• •••••••••••••••••••• ••••••••••••• •••••••••••••••• •• •••••• ••••• •• •••••••••••••••••••••••
Used in combination to treatAcute lymphoblastic leukemia•••••••••••••••••• •••••••••••••••••••• ••••••••••••• ••••••••• ••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Unlike normal cells, leukemia cells are dependent on an exogenous source of asparagine for survival. Pegaspargase hydrolyses asparagine into aspartic acid and ammonia, which depletes asparagine levels and leads to leukaemic cell death.3 In patients given intramuscular doses of 2,500 International Units(IU)/m2 of pegaspargase, the serum levels of asparagine fall at day 4 and remain depleted for about 3 weeks. In adult patients with acute lymphocytic leukemia given 2,000 IU/m2 of pegaspargase intravenously, the deamination of asparagine takes place 2 h after administration and is sustained for 3 weeks, while in pediatric patients given 2,500 IU/m2, levels are sustained for 5 weeks.4 The use of pegaspargase may lead to thrombosis, pancreatitis, glucose intolerance, hemorrhage, hepatotoxicity, anaphylaxis and serious hypersensitivity reactions.5

Mechanism of action

Pegaspargase is a pegylated L-asparaginase that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. Asparagine is an amino acid that is vital for DNA and RNA synthesis and cell division. It is not an essential amino acid in humans since most normal human tissues can produce asparagine via the enzyme asparagine synthetase. However, leukemia cells have low levels of this enzyme and are unable to synthesize asparagine, making them dependent on exogenous sources. It has been suggested that pegaspargase kills leukemic cells by depleting plasma asparagine.1,2,5 Both Escherichia coli-derived L-asparaginase and pegaspargase follow the same mechanism of action; however, Escherichia coli-derived L-asparaginase requires frequent administration, presents a high incidence of hypersensitivity reactions, and can be neutralized without any signs of hypersensitivity. By pegylating L-asparaginase, the circulation time of L-asparaginase can be extended, and immunogenicity is reduced.3

TargetActionsOrganism
AL-asparagine
substrate
Humans
Absorption

In patients with acute lymphoblastic leukemia given 2,500 International Units (IU)/m2 of pegaspargase, the mean asparaginase Cmax was reached at approximately 1 IU/mL (n=45-52) five days after a single intramuscular injection. Pegaspargase had a relative bioavailability of 82% after the first intramuscular dose and 98% following repeat dosing. In patients given pegaspargase intravenously in a single infusion (n=47) during the induction phase, the mean Cmax and AUC0-inf were 1.6 IU/mL and 16.6 IU/mL⋅day, respectively.5 The Tmax for these patients was 1.25 hr.6 The impact of renal and hepatic impairment on pegaspargase pharmacokinetics is unknown.5

Volume of distribution

Based on a non-compartmental analysis, pegaspargase has a steady-state volume of distribution of approximately 1.86 L/m2 after a single intramuscular injection and 2 L after a single intravenous infusion.5

Protein binding

Not Available

Metabolism

As a pegylated form of L-asparaginase, pegaspargase is expected to be metabolized by proteolytic enzymes throughout the body. Since these enzymes are ubiquitously distributed, the exact role of the liver is unknown.6

Route of elimination

Due to its high molecular weight, pegaspargase is not excreted renally.6

Half-life

The mean elimination half-life of pegaspargase was approximately 5.8 days after a single intramuscular dose, and 5.3 days after a single intravenous dose.5

Clearance

For a single intramuscular and intravenous dose, the clearance of pegaspargase is 0.17 L/m2/day and 0.2 L/day, respectively.5

Adverse Effects
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Toxicity

Patients that received 10,000 International Units/m2 of pegaspargase intravenously, had a slight increase in liver enzymes and a rash that developed 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. There is no specific antidote for pegaspargase overdosage. The product label recommends to monitor patients closely for signs and symptoms of adverse reactions, and appropriately manage with symptomatic and supportive treatment in case of overdose. The carcinogenic, mutagenic and fertility effects of pegaspargase have not been evaluated.5

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
AbataceptThe risk or severity of adverse effects can be increased when Pegaspargase is combined with Abatacept.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Pegaspargase.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Pegaspargase.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Pegaspargase.
AlefaceptThe risk or severity of adverse effects can be increased when Pegaspargase is combined with Alefacept.
Food Interactions
  • Avoid excessive or chronic alcohol consumption. Alcohol and pegaspargase can both cause hepatoxicity, therefore if they are used together they may have additive hepatoxic effects.

Products

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International/Other Brands
Oncaspar (Servier Pharmaceuticals)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Lyophilized PegaspargaseInjection, powder, lyophilized, for solution750 [iU]/1mLIntravenousServier Pharmaceuticals2020-08-03Not applicableUS flag
Lyophilized PegaspargaseInjection, powder, lyophilized, for solution750 U/1mLIntramuscularBaxalta US Inc.2018-02-072020-05-16US flag
OncasparLiquid750 unit / mLIntramuscular; IntravenousAventis Pharma Ltd.1998-10-132004-01-02Canada flag
OncasparInjection, solution750 [iU]/1mLIntramuscular; IntravenousSigma Tau Pharmaceuticals, Inc.1994-02-012016-11-30US flag
Oncaspar750 U/mlLes Laboratoires Servier2020-12-16Not applicableEU flag

Categories

ATC Codes
L01XX24 — Pegaspargase
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
7D96IR0PPM
CAS number
130167-69-0

References

General References
  1. Graham ML: Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev. 2003 Sep 26;55(10):1293-302. [Article]
  2. Zeidan A, Wang ES, Wetzler M: Pegasparaginase: where do we stand? Expert Opin Biol Ther. 2009 Jan;9(1):111-9. doi: 10.1517/14712590802586058. [Article]
  3. Heo YA, Syed YY, Keam SJ: Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs. 2019 May;79(7):767-777. doi: 10.1007/s40265-019-01120-1. [Article]
  4. Fu CH, Sakamoto KM: PEG-asparaginase. Expert Opin Pharmacother. 2007 Aug;8(12):1977-84. doi: 10.1517/14656566.8.12.1977. [Article]
  5. FDA Approved Drug Products: ONCASPAR (pegaspargase) injection for intramuscular or intravenous use [Link]
  6. EMA Summary of Product Characteristics: Oncaspar (pegaspargase) powder for solution for injection/infusion [Link]
UniProt
P37595
Genbank
U00096
PubChem Substance
46505366
RxNav
34132
ChEMBL
CHEMBL2108546
PharmGKB
PA164760860
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pegaspargase

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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4RecruitingTreatmentHemophagocytic Syndrome (HPS) / NK/T-cell Lymphoma1somestatusstop reasonjust information to hide
4Unknown StatusTreatmentAcute Lymphoblastic Leukemia (ALL)1somestatusstop reasonjust information to hide
4Unknown StatusTreatmentExtranodal NK/T-cell Lymphoma, Nasal Type1somestatusstop reasonjust information to hide
4Unknown StatusTreatmentNeoplasms, Hematologic1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL) / Acute Undifferentiated Leukemia (AUL) / T-cell Childhood Acute Lymphoblastic Leukemia1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Ben Venue Laboratories Inc.
  • Enzon Inc.
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntramuscular750 U/1mL
Injection, powder, lyophilized, for solutionIntravenous750 [iU]/1mL
Injection, powder, for solutionIntramuscular; Intravenous750 U/ML
Injection, solutionIntramuscular; Intravenous750 U/ML
Injection, solutionIntramuscular; Intravenous750 [iU]/1mL
LiquidIntramuscular; Intravenous750 unit / mL
SolutionIntramuscular; Intravenous750 unit / mL
SolutionIntramuscular; Intravenous750 IU
Powder750 U/ml
Injection, powder, lyophilized, for solutionIntramuscular; Intravenous750 U/ml
Injection, powder, lyophilized, for solutionIntramuscular; Intravenous750 U
Prices
Unit descriptionCostUnit
Oncaspar 750 unit/ml vial656.0USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity0.059Not Available
isoelectric point4.67Not Available

Targets

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Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Douer D, Yampolsky H, Cohen LJ, Watkins K, Levine AM, Periclou AP, Avramis VI: Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood. 2007 Apr 1;109(7):2744-50. [Article]
  4. Wetzler M, Sanford BL, Kurtzberg J, DeOliveira D, Frankel SR, Powell BL, Kolitz JE, Bloomfield CD, Larson RA: Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007 May 15;109(10):4164-7. Epub 2007 Jan 30. [Article]
  5. Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R: FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007 Aug;12(8):991-8. [Article]
  6. FDA Approved Drug Products: ONCASPAR (pegaspargase) injection for intramuscular or intravenous use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Based on interaction with L-asparaginase
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da
References
  1. Bartalena L, Martino E, Antonelli A, Pacchiarotti A, Robbins J, Pinchera A: Effect of the antileukemic agent L-asparaginase on thyroxine-binding globulin and albumin synthesis in cultured human hepatoma (HEP G2) cells. Endocrinology. 1986 Sep;119(3):1185-8. doi: 10.1210/endo-119-3-1185. [Article]
  2. Garnick MB, Larsen PR: Acute deficiency of thyroxine-binding globulin during L-asparaginase therapy. N Engl J Med. 1979 Aug 2;301(5):252-3. doi: 10.1056/NEJM197908023010506. [Article]

Drug created at June 13, 2005 13:24 / Updated at April 23, 2024 11:38