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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Acute lymphoblastic leukemia •••••••••••• •••••• ••••••••• ••••••••••• ••••••••••••• •••••••••••••••• •• •••••• ••••• •• •••••••••••••• ••••••••• Used in combination to treat Acute 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
Target Actions Organism AL-asparagine substrateHumans - 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Pegaspargase is combined with Abatacept. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Pegaspargase. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Pegaspargase. Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Pegaspargase. Alefacept The 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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Oncaspar (Servier Pharmaceuticals)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Lyophilized Pegaspargase Injection, powder, lyophilized, for solution 750 [iU]/1mL Intravenous Servier Pharmaceuticals 2020-08-03 Not applicable US Lyophilized Pegaspargase Injection, powder, lyophilized, for solution 750 U/1mL Intramuscular Baxalta US Inc. 2018-02-07 2020-05-16 US Oncaspar Injection, solution 750 [iU]/1mL Intramuscular; Intravenous Servier Pharmaceuticals LLC 2020-01-02 Not applicable US Oncaspar Injection, solution 750 [iU]/1mL Intramuscular; Intravenous Sigma Tau Pharmaceuticals, Inc. 1994-02-01 2016-11-30 US Oncaspar 750 U/ml Les Laboratoires Servier 2020-12-16 Not applicable EU
Categories
- ATC Codes
- L01XX24 — Pegaspargase
- Drug Categories
- Alcohols
- Amidohydrolases
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Asparaginase
- Asparagine-specific Enzyme
- Compounds used in a research, industrial, or household setting
- Delayed-Action Preparations
- Enzymes
- Enzymes and Coenzymes
- Ethylene Glycols
- Glycols
- Hydrolases
- Immunosuppressive Agents
- Macromolecular Substances
- Pegylated agents
- Polymers
- Thyroxine-binding globulin inhibitors
- 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
- Graham ML: Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev. 2003 Sep 26;55(10):1293-302. [Article]
- 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]
- 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]
- Fu CH, Sakamoto KM: PEG-asparaginase. Expert Opin Pharmacother. 2007 Aug;8(12):1977-84. doi: 10.1517/14656566.8.12.1977. [Article]
- FDA Approved Drug Products: ONCASPAR (pegaspargase) injection for intramuscular or intravenous use [Link]
- EMA Summary of Product Characteristics: Oncaspar (pegaspargase) powder for solution for injection/infusion [Link]
- External Links
- UniProt
- P37595
- Genbank
- U00096
- PubChem Substance
- 46505366
- 34132
- ChEMBL
- CHEMBL2108546
- PharmGKB
- PA164760860
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Pegaspargase
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Recruiting Treatment Hemophagocytic Syndrome (HPS) / NK/T-cell Lymphoma 1 4 Unknown Status Treatment Acute Lymphoblastic Leukaemias (ALL) 1 4 Unknown Status Treatment Extranodal NK/T-cell Lymphoma, Nasal Type 1 4 Unknown Status Treatment Neoplasms, Hematologic 1 3 Active Not Recruiting Treatment Acute Lymphoblastic Leukaemias (ALL) / Acute Undifferentiated Leukemia (AUL) / T-cell Childhood Acute Lymphoblastic Leukemia 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Ben Venue Laboratories Inc.
- Enzon Inc.
- Dosage Forms
Form Route Strength Injection, powder, lyophilized, for solution Intramuscular 750 U/1mL Injection, powder, lyophilized, for solution Intravenous 750 [iU]/1mL Injection, powder, for solution Intramuscular; Intravenous 750 U/ML Injection, solution Intramuscular; Intravenous 750 U/ML Injection, solution Intramuscular; Intravenous 750 [iU]/1mL Liquid Intramuscular; Intravenous 750 unit / mL Solution Intramuscular; Intravenous 750 unit / mL Solution Intramuscular; Intravenous 750 IU Injection, powder, lyophilized, for solution Intramuscular; Intravenous 750 U/ml Injection, powder, lyophilized, for solution Intramuscular; Intravenous 750 U - Prices
Unit description Cost Unit Oncaspar 750 unit/ml vial 656.0USD ml DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
Property Value Source hydrophobicity 0.059 Not Available isoelectric point 4.67 Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- 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]
- 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]
- 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]
- 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]
- 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
- 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]
- 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 February 20, 2024 23:54