Pegfilgrastim

Identification

Summary

Pegfilgrastim is a recombinant human granulocyte colony stimulating factor used to stimulate the production of neutrophils and prevent febrile neutropenia or infections after myelosuppressive chemotherapy.

Brand Names
Fulphila, Neulasta, Udenyca, Ziextenzo
Generic Name
Pegfilgrastim
DrugBank Accession Number
DB00019
Background

Pegfilgrastim is a PEGylated form of the recombinant human granulocyte colony-stimulating factor (G-CSF) analogue, filgrastim.2 It is used to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with with non-myeloid cancer receiving myelosuppressive anti-cancer treatment. Some patients with greater risk factors may develop febrile neutropenia from myelosuppressive therapy and are susceptible to an increased risk of developing infections. Although the risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens,9 infections pose risks of hospitalization and mortalities.4 Due to the relatively short circulating half-life of filgrastim, a 20 kDa PEG moiety was covalently conjugated to the N-terminus of filgrastim (at the methionine residue) to develop a longer acting version of the drug.1,3 Due to a longer half-life and slower elimination rate than filgrastim, pegfilgrastim requires less frequent dosing than filgrastim. However, pegfilgrastim retains the same biological activity as filgrastim and binds to the same G-CSF receptor to stimulate the proliferation, differentiation, and activation of neutrophils.3

First developed by Amgen, pegfilgrastim was initially approved by the FDA in 2002 and marketed as Neulasta®. It is typically administered via a subcutaneous injection. There are several pegfilgrastim biosimilars (Fulphila®, Pelgraz® or Lapelga®, Pelmeg®, Udenyca®, Ziextenzo®, and Grasustek®) that are approved for the same therapeutic indication by Health Canada, European Union (EU), and FDA.8,10 These biosimilars are highly similar to the reference product, Neulasta®, in terms of pharmacological and pharmacokinetic profile and condition(s) of use, such as the therapeutic indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s) of administration.11

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Haematopoietic growth factors
Protein Structure
Db00019
Protein Chemical Formula
C845H1343N223O243S9
Protein Average Weight
39000.0 Da (approximate, PEGylated)
Sequences
> Pegfilgrastim sequence
MTPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLCATYKLCHPEELVLLGHSLGIPWA
PLSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQ
QMEELGMAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFLEVSYRVLRHLAQP
Download FASTA Format
Synonyms
  • Granulocyte colony-stimulating factor pegfilgrastim
  • peg-filgrastim
  • Pegfilgrastim
  • pegfilgrastim-apgf
  • pegfilgrastim-bmez
  • pegfilgrastim-cbqv
  • pegfilgrastim-jmdb

Pharmacology

Indication

Pegfilgrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non­ myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.6

It is also indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome).6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Pegfilgrastim is a recombinant human granulocyte colony-stimulating factor (G-CSF) that promotes the production, proliferation, and maturation of neutrophils, which are white blood cells involved in both innate and adaptive immune responses.4,9 The safety and efficacy of pegfilgrastim in reducing the risk of febrile neutropenia and infections have been demonstrated in various tumor types and settings.4

During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until the onset of neutrophil recovery.1 Serum concentrations of pegfilgrastim decline as the neutrophil count increases as neutrophil and neutrophil precursors are involved in cell-mediated clearance of the drug.2 Due the addition of polyethylene glycol group to its structure, Pegfilgrastim is a long-acting form of filgrastim with an extended serum half-life and reduced renal clearance.3 Although it is more slowly absorbed than filgrastim, self-regulation of pegfilgrastim is more efficient and the drug effects are maintained during one chemotherapy cycle (2-3 weeks).1

Mechanism of action

Neutrophils are short-lived immune cells that are highly susceptible to cell death following myelosuppressive chemotherapy. This marked reduction in neutrophil numbers during chemotherapy increases the risk of hospitalization, infection, and infection-related mortality. It also directly impacts the clinical outcome of patients if cases of febrile neutropenia requires dose reductions or schedule delay of chemotherapy, thus reducing the clinical efficacy of chemotherapy and patient benefit from receiving appropriate treatment.4

G-CSF is an endogenous haematopoietic growth factor that stimulates granulopoietic cells of the neutrophil lineage. Pegfilgrastim mimics its biological actions and binds to the same G-CSF receptor expressed on cells of myeloid lineage, such as granulocytic precursors and mature neutrophils.1 Upon binding of the ligand, G-CSF receptor undergoes a conformational change and activates several downstream signalling pathways including JAK/STAT, PI3K/AKT and MAPK/ERK.5 These pathways work to increase proliferation and differentiation of granulocyte progenitor cells, induce maturation of the progenitor cells, and enhance survival and function of mature neutrophils.1

TargetActionsOrganism
AGranulocyte colony-stimulating factor receptor
agonist
Humans
Absorption

Pegfilgrastim has a lower absolute bioavailability than filgrastim following subcutaneous administration. The absorption of pegfilgrastim is largely dependent on the lymphatic system due to the attached PEG group contributing to the large size of the drug. It is slowly absorbed following subcutaneous administration with a time to peak concentration (Tmax) of about 1-2 days.1

Volume of distribution

Pegfilgrastim appears to have a volume of distribution of approximately 170L.[A33290]

Protein binding

The plasma protein binding of pegfilgrastim is unlikely.12

Metabolism

It is not know whether pegfilgrastim is metabolized into major metabolites.12 Once it binds to the therapeutic target, pegfilgrastim is internalized by the neutrophil and undergoes nonspecific degradation.1

Route of elimination

The polyethylene glycol moiety limits the renal clearance by glomerular filtration of pegfilgrastim, making neutrophil-mediated clearance as the predominant route of elimination.3 This elimination pathway is initiated by the binding of pegfilgrastim to the G-CSF receptor on the neutrophil cell surface, leading to the internalization of the pegfilgrastim-receptor complex via endocytosis and subsequent degradation inside the cell. While hepatic clearance has not been well characterized for pegfilgrastim, its non-PEGylated precursor filgrastim is known to be unaffected by changes in hepatic clearance.1

Half-life

The serum half-life of Pegfilgrastim is highly variable depending on the absolute neutrophil count, with the range of 15 to 80 hours following subcutaneous administration. The median serum half-life of 42 hours.3,6

Clearance

Pegfilgrastim has a self-regulating clearance that involves neutrophil-induced clearance.1,4 The clearance is dependent on the number of neutrophils and body weight of the patient: the clearance increases with increasing number of granulocytes and lower body weights.6 Pegfilgrastim is not eliminated from the circulation until neutrophils start to recover following chemotherapy-induced neutropenia and its clearance is increased as neutrophil counts also increase.4 The apparent serum clearance is 14 mL/h/kg.12

Adverse Effects
Adverseeffects
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Toxicity

The maximum safe dose of pegfilgrastim has not been established; however, the highest dose used in clinical trials was 300 mcg/kg.9 Overdosage of pegfilgrastim may result in leukocytosis and bone pain. Events of edema, dyspnea, and pleural effusion have been reported in a single patient who self-administered pegfilgrastim on 8 consecutive days in error. In the event of overdose, the patient should be monitored for signs and symptoms of toxicity and responded with appropriate general supportive care.6,9

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
Antihemophilic factor (recombinant), PEGylatedThe therapeutic efficacy of Antihemophilic factor (recombinant), PEGylated can be decreased when used in combination with Pegfilgrastim.
Certolizumab pegolThe therapeutic efficacy of Certolizumab pegol can be decreased when used in combination with Pegfilgrastim.
CyclophosphamideThe risk or severity of pulmonary toxicity can be increased when Pegfilgrastim is combined with Cyclophosphamide.
Damoctocog alfa pegolThe therapeutic efficacy of Damoctocog alfa pegol can be decreased when used in combination with Pegfilgrastim.
ElapegademaseThe therapeutic efficacy of Elapegademase can be decreased when used in combination with Pegfilgrastim.
LipegfilgrastimThe therapeutic efficacy of Lipegfilgrastim can be decreased when used in combination with Pegfilgrastim.
Methoxy polyethylene glycol-epoetin betaThe therapeutic efficacy of Methoxy polyethylene glycol-epoetin beta can be decreased when used in combination with Pegfilgrastim.
Nonacog beta pegolThe therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Pegfilgrastim.
PegademaseThe therapeutic efficacy of Pegademase can be decreased when used in combination with Pegfilgrastim.
PegaptanibThe therapeutic efficacy of Pegaptanib can be decreased when used in combination with Pegfilgrastim.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CegfilaInjection, solution6 mgSubcutaneousMundipharma Corporation (Ireland) Limited2020-12-16Not applicableEU flag
FulphilaInjection, solution6 mgSubcutaneousMylan S.A.S.2020-12-16Not applicableEU flag
FulphilaInjection, solution6 mgSubcutaneousMylan S.A.S.2020-12-16Not applicableEU flag
FulphilaInjection6 mg/0.6mLSubcutaneousMylan Institutional LLC2018-07-09Not applicableUS flag
FulphilaSolution10 mg / mLSubcutaneousBgp Pharma Ulc2020-02-07Not applicableCanada flag
GrasustekInjection, solution6 mgSubcutaneousJuta Pharma Gmb H2020-12-16Not applicableEU flag
LapelgaSolution6 mg / 0.6 mLSubcutaneousApotex Corporation2019-02-27Not applicableCanada flag
NeulastaKit6 mg/0.6mLSubcutaneousAMGEN INC2002-04-01Not applicableUS flag
NeulastaInjection, solution6 mgSubcutaneousAmgen Europe B.V.2020-12-16Not applicableEU flag
NeulastaInjection6 mg/0.6mLSubcutaneousAMGEN INC2002-04-01Not applicableUS flag

Categories

ATC Codes
L03AA13 — Pegfilgrastim
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
3A58010674
CAS number
208265-92-3

References

General References
  1. Yang BB, Kido A: Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet. 2011 May;50(5):295-306. doi: 10.2165/11586040-000000000-00000. [Article]
  2. Curran MP, Goa KL: Pegfilgrastim. Drugs. 2002;62(8):1207-13; discussion 1214-5. doi: 10.2165/00003495-200262080-00012. [Article]
  3. Molineux G: The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des. 2004;10(11):1235-44. doi: 10.2174/1381612043452613. [Article]
  4. Arvedson T, O'Kelly J, Yang BB: Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor. BioDrugs. 2015 Jun;29(3):185-98. doi: 10.1007/s40259-015-0127-4. [Article]
  5. Dwivedi P, Greis KD: Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies. Exp Hematol. 2017 Feb;46:9-20. doi: 10.1016/j.exphem.2016.10.008. Epub 2016 Oct 24. [Article]
  6. Neulasta (pegfilgrastim) - FDA Label [Link]
  7. Neulasta Safety Data Sheet - Amgen [Link]
  8. Biosimilars of pegfilgrastim [Link]
  9. Pegfilgrastim - StatPearls - NCBI Bookshelf [Link]
  10. EMA approval for pegfilgrastim biosimilar Grasustek [Link]
  11. Biosimilar and Interchangeable Products | FDA [Link]
  12. pegfilgrastim | Cancer Care Ontario [Link]
UniProt
P09919
Genbank
X03438
KEGG Drug
D06889
PubChem Substance
46505853
RxNav
338036
ChEMBL
CHEMBL1201568
Therapeutic Targets Database
DAP000395
PharmGKB
PA164781387
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pegfilgrastim

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionBreast Cancer2
4CompletedPreventionBreast Cancer / Lung Cancers / Neutropenia / Non-Hodgkin's Lymphoma (NHL) / Ovarian Cancer1
4CompletedPreventionMalignant Lymphomas1
4CompletedPreventionSolid Malignant Tumors1
4CompletedTreatmentBreast Cancer1
4CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
4CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
4RecruitingTreatmentEarly Breast Cancer1
4Unknown StatusSupportive CareBreast Cancer / Neutropenia1
3Active Not RecruitingSupportive CareChemotherapy Induced Neutropenia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amgen Inc.
  • Physicians Total Care Inc.
Dosage Forms
FormRouteStrength
Solution
SolutionSubcutaneous6 mg / 0.6 mL
InjectionSubcutaneous6 mg/0.6mL
Injection, solutionSubcutaneous6 MG
KitSubcutaneous6 mg/0.6mL
SolutionParenteral; Subcutaneous6 MG
SolutionSubcutaneous10 mg / mL
InjectionSubcutaneous
SolutionSubcutaneous6 mg
Injection, solutionSubcutaneous
SolutionSubcutaneous10 mg
Solution5 mg/1ml
Injection, solutionParenteral; Subcutaneous6 MG
Injection, solutionSubcutaneous6 mg/0.6mL
Injection, solution6 mg/0.6ml
Prices
Unit descriptionCostUnit
Neulasta 6 mg/0.6 ml syringe4102.37USD syringe
Neulasta 6 mg/0.6ml Solution 0.6ml Syringe4026.05USD syringe
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA1341537No2007-07-312024-07-31Canada flag
CA1339071No1997-07-292014-07-29Canada flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)60 °CLuo, P., Protein Science 11:1218-1226 (2002)

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor activity
Specific Function
Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differientation and survival of cells along the neutroph...
Gene Name
CSF3R
Uniprot ID
Q99062
Uniprot Name
Granulocyte colony-stimulating factor receptor
Molecular Weight
92155.615 Da
References
  1. Erkeland SJ, Aarts LH, Irandoust M, Roovers O, Klomp A, Valkhof M, Gits J, Eyckerman S, Tavernier J, Touw IP: Novel role of WD40 and SOCS box protein-2 in steady-state distribution of granulocyte colony-stimulating factor receptor and G-CSF-controlled proliferation and differentiation signaling. Oncogene. 2007 Mar 29;26(14):1985-94. Epub 2006 Sep 25. [Article]
  2. Elsasser A, Franzen M, Kohlmann A, Weisser M, Schnittger S, Schoch C, Reddy VA, Burel S, Zhang DE, Ueffing M, Tenen DG, Hiddemann W, Behre G: The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner. Oncogene. 2003 Aug 28;22(36):5646-57. [Article]
  3. Ward AC: The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease. Front Biosci. 2007 Jan 1;12:608-18. [Article]
  4. Zhuang D, Qiu Y, Haque SJ, Dong F: Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1. J Leukoc Biol. 2005 Oct;78(4):1008-15. Epub 2005 Jul 20. [Article]
  5. Cao YR, Shao ZH, Liu H, Shi J, Bai J, Tu MF, Wang HQ, Xing LM, Cui ZZ, Sun J, Jia HR, Yang TY: [The response of bone marrow hematopoietic cells to G-CSF in paroxysmal nocturnal hemoglobinuria patients]. Zhonghua Xue Ye Xue Za Zhi. 2005 Apr;26(4):235-8. [Article]
  6. Kotto-Kome AC, Fox SE, Lu W, Yang BB, Christensen RD, Calhoun DA: Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model. Pharmacol Res. 2004 Jul;50(1):55-8. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.
Gene Name
ELANE
Uniprot ID
P08246
Uniprot Name
Neutrophil elastase
Molecular Weight
28517.81 Da
References
  1. Carter CR, Whitmore KM, Thorpe R: The significance of carbohydrates on G-CSF: differential sensitivity of G-CSFs to human neutrophil elastase degradation. J Leukoc Biol. 2004 Mar;75(3):515-22. Epub 2003 Dec 4. [Article]
  2. Jian MY, Koizumi T, Tsushima K, Fujimoto K, Kubo K: Effects of granulocyte colony-stimulating factor (G-CSF) and neutrophil elastase inhibitor (ONO-5046) on acid-induced lung injury in rats. Inflammation. 2004 Dec;28(6):327-36. [Article]
  3. Pelus LM, Bian H, King AG, Fukuda S: Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2delta4. Blood. 2004 Jan 1;103(1):110-9. Epub 2003 Sep 4. [Article]
  4. Druhan LJ, Ai J, Massullo P, Kindwall-Keller T, Ranalli MA, Avalos BR: Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. Blood. 2005 Jan 15;105(2):584-91. Epub 2004 Sep 7. [Article]
  5. Schepers H, Wierenga AT, van Gosliga D, Eggen BJ, Vellenga E, Schuringa JJ: Reintroduction of C/EBPalpha in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis. Blood. 2007 Aug 15;110(4):1317-25. Epub 2007 May 2. [Article]
  6. Abdolzade-Bavil A, von Kerczek A, Cooksey BA, Kaufman T, Krasney PA, Pukac L, Gorlach M, Lammerich A, Scheckermann C, Allgaier H, Shen WD, Liu PM: Differential sensitivity of lipegfilgrastim and pegfilgrastim to neutrophil elastase correlates with differences in clinical pharmacokinetic profile. J Clin Pharmacol. 2016 Feb;56(2):186-94. doi: 10.1002/jcph.578. Epub 2015 Sep 1. [Article]

Drug created on June 13, 2005 13:24 / Updated on September 19, 2021 19:53