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, Fylnetra, 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 The drug is approved for use to decrease the incidence of infection, as manifested by febrile neutropenia, in susceptible patients with with non-myeloid cancer receiving myelosuppressive anti-cancer treatment.⁸ Although the risk of developing febrile neutropenia is less than 20% in many readily used chemotherapy regimens,⁷ 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 longer-acting pegfilgrastim.^1,3 Due to a longer half-life and slower elimination rate than filgrastim, pegfilgrastim requires less frequent dosing than filgrastim; however, pegfilgrastim has a comparable pharmacological activity to filgrastim and binds to the 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, Grasustek, Fylnetra, Stimufend) by Health Canada, European Union (EU), and FDA that are approved to reduce infection risk.^10,11,14 These biosimilars are highly similar to the reference product, Neulasta, in terms of pharmacological and pharmacokinetic profile and conditions of use.¹²

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Haematopoietic growth factors

Protein Structure

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.⁸

It is also indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome).⁸

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Associated Conditions

Contraindications & Blackbox Warnings

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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.^4,7 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

Target	Actions	Organism
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 (T_max) of about one to two days.¹

Volume of distribution

Pegfilgrastim appears to have a volume of distribution of approximately 170 L.⁶

Protein binding

The plasma protein binding of pegfilgrastim is unlikely.¹³

Metabolism

It is not know whether pegfilgrastim is metabolized into major metabolites.¹³ 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.^3,8

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.⁸ 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.¹³

Adverse Effects

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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.⁷ 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.^8,7

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.

Drug	Interaction
Integrate drug-drug interactions in your software
Antihemophilic factor (recombinant), PEGylated	The therapeutic efficacy of Antihemophilic factor (recombinant), PEGylated can be decreased when used in combination with Pegfilgrastim.
Certolizumab pegol	The therapeutic efficacy of Certolizumab pegol can be decreased when used in combination with Pegfilgrastim.
Cyclophosphamide	The risk or severity of pulmonary toxicity can be increased when Pegfilgrastim is combined with Cyclophosphamide.
Damoctocog alfa pegol	The therapeutic efficacy of Damoctocog alfa pegol can be decreased when used in combination with Pegfilgrastim.
Elapegademase	The therapeutic efficacy of Elapegademase can be decreased when used in combination with Pegfilgrastim.
Lipegfilgrastim	The therapeutic efficacy of Lipegfilgrastim can be decreased when used in combination with Pegfilgrastim.
Methoxy polyethylene glycol-epoetin beta	The therapeutic efficacy of Methoxy polyethylene glycol-epoetin beta can be decreased when used in combination with Pegfilgrastim.
Nonacog beta pegol	The therapeutic efficacy of Nonacog beta pegol can be decreased when used in combination with Pegfilgrastim.
Pegademase	The therapeutic efficacy of Pegademase can be decreased when used in combination with Pegfilgrastim.
Pegaptanib	The therapeutic efficacy of Pegaptanib can be decreased when used in combination with Pegfilgrastim.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Cegfila	Injection, solution	6 mg	Subcutaneous	Mundipharma Corporation (Ireland) Limited	2020-12-16	Not applicable
Fulphila	Injection, solution	6 mg	Subcutaneous	Viatris Limited	2020-12-16	Not applicable
Fulphila	Injection	6 mg/0.6mL	Subcutaneous	Mylan Institutional LLC	2018-07-09	Not applicable
Fulphila	Solution	10 mg / mL	Subcutaneous	Bgp Pharma Ulc	2020-02-07	Not applicable
Fulphila	Injection, solution	6 mg	Subcutaneous	Viatris Limited	2020-12-16	Not applicable
Fylnetra	Injection	6 mg/0.6mL	Subcutaneous	Amneal Pharmaceuticals LLC	2022-05-31	Not applicable
Grasustek	Injection, solution	6 mg	Subcutaneous	Juta Pharma Gmb H	2020-12-16	Not applicable
Lapelga	Solution	6 mg / 0.6 mL	Subcutaneous	Apotex Corporation	2019-02-27	Not applicable
Lapelga	Solution	6 mg / 0.6 mL	Subcutaneous	Apotex Corporation	Not applicable	Not applicable
Neulasta	Injection, solution	6 mg	Subcutaneous	Amgen Europe B.V.	2020-12-16	Not applicable

Chemical Identifiers

UNII: 3A58010674
CAS number: 208265-92-3

References

General References

Yang BB, Kido A: Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet. 2011 May;50(5):295-306. doi: 10.2165/11586040-000000000-00000. [Article]
Curran MP, Goa KL: Pegfilgrastim. Drugs. 2002;62(8):1207-13; discussion 1214-5. doi: 10.2165/00003495-200262080-00012. [Article]
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]
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]
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]
Waller CF, Tiessen RG, Lawrence TE, Shaw A, Liu MS, Sharma R, Baczkowski M, Kothekar MA, Micales CE, Barve A, Ranganna GM, Pennella EJ: A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim. J Cancer Res Clin Oncol. 2018 Jun;144(6):1087-1095. doi: 10.1007/s00432-018-2643-3. Epub 2018 Apr 18. [Article]
Parker SD, King N, Jacobs TF: Pegfilgrastim . [Article]
FDA Approved Drug Products: NEULASTA (pegfilgrastim) injection, for subcutaneous use [Link]
Amgen: Neulasta (pegfilgrastim) MSDS [Link]
GENERICS AND BIOSIMILARS INITIATIVE: Biosimilars of pegfilgrastim [Link]
GENERICS AND BIOSIMILARS INITIATIVE: EMA approval for pegfilgrastim biosimilar Grasustek [Link]
FDA: Biosimilar and Interchangeable Products [Link]
Cancer Care Ontario Drug Information: Pegfilgrastim [Link]
FDA Approved Drug Products: STIMUFEND (pegfilgrastim-fpgk) injection, for subcutaneous use [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Completed	Prevention	Breast Cancer	2
4	Completed	Prevention	Breast Cancer / Lung Cancers / Neutropenia / Non-Hodgkin's Lymphoma (NHL) / Ovarian Cancer	1
4	Completed	Prevention	Malignant Lymphomas	1
4	Completed	Prevention	Solid Malignant Tumors	1
4	Completed	Treatment	Breast Cancer	1
4	Completed	Treatment	Non-Hodgkin's Lymphoma (NHL)	1
4	Completed	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1
4	Recruiting	Treatment	Early Breast Cancer	1
4	Unknown Status	Supportive Care	Breast Cancer / Neutropenia	1
3	Active Not Recruiting	Supportive Care	Chemotherapy Induced Neutropenia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Amgen Inc.
Physicians Total Care Inc.

Dosage Forms

Form	Route	Strength
Solution
Solution	Subcutaneous	6 mg / 0.6 mL
Injection	Subcutaneous	6 mg/0.6mL
Injection, solution	Subcutaneous	6 MG
Kit	Subcutaneous	6 mg/0.6mL
Solution	Parenteral; Subcutaneous	6 MG
Solution	Subcutaneous	10 mg / mL
Injection	Subcutaneous
Solution	Subcutaneous	6 mg
Injection, solution	Subcutaneous
Solution	Subcutaneous	10 mg
Solution		5 mg/1ml
Injection, solution	Parenteral; Subcutaneous	6 MG
Injection, solution	Subcutaneous	6 mg/0.6mL
Injection, solution		6 mg/0.6ml

Prices

Unit description	Cost	Unit
Neulasta 6 mg/0.6 ml syringe	4102.37USD	syringe
Neulasta 6 mg/0.6ml Solution 0.6ml Syringe	4026.05USD	syringe

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA1341537	No	2007-07-31	2024-07-31
CA1339071	No	1997-07-29	2014-07-29

Properties

State

Liquid

Experimental Properties

Property	Value	Source
melting point (°C)	60 °C	Luo, P., Protein Science 11:1218-1226 (2002)

Targets

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insights and accelerate drug research.

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Details1. Granulocyte colony-stimulating factor receptor

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

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]
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]
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]
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]
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]
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

Details1. Neutrophil elastase

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

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]
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]
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]
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]
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]
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 at June 13, 2005 13:24 / Updated at September 07, 2022 02:10

Pegfilgrastim

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

Enzymes

References