Pegfilgrastim

Identification

Name

Pegfilgrastim

Accession Number

DB00019

Description

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

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-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

Associated Conditions

• Chemotherapy Induced Neutropenia
• Hematopoietic Subsyndrome of Acute Radiation Syndrome
• Infection

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.^4,9 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

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 (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

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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

Affected organisms

• Humans and other mammals

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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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.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
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Action
Action
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Food Interactions

No interactions found.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
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Fulphila	Injection	6 mg/0.6mL	Subcutaneous	Mylan Institutional LLC	2018-07-09	Not applicable
Fulphila	Solution	10 mg	Subcutaneous	Bgp Pharma Ulc	2020-02-07	Not applicable
Lapelga	Solution		Subcutaneous	Apotex Corporation	2019-02-27	Not applicable
Neulasta	Injection	6 mg/0.6mL	Subcutaneous	Physicians Total Care, Inc.	2006-02-23	2011-12-31
Neulasta	Injection	6 mg/0.6mL	Subcutaneous	AMGEN INC	2002-04-01	Not applicable
Neulasta	Solution	10 mg	Subcutaneous	Amgen	2004-03-12	Not applicable
Neulasta	Kit	6 mg/0.6mL	Subcutaneous	AMGEN INC	2002-04-01	Not applicable
Neupopeg	Injection, solution	6 mg	Subcutaneous	Dompé Biotec S.P.A.	2002-08-22	2008-12-22
Neupopeg	Injection, solution	6 mg	Subcutaneous	Dompé Biotec S.P.A.	2002-08-22	2008-12-22
Neupopeg	Injection, solution	6 mg	Subcutaneous	Dompé Biotec S.P.A.	2002-08-22	2008-12-22

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L03AA13 — Pegfilgrastim

• L03AA — Colony stimulating factors
• L03A — IMMUNOSTIMULANTS
• L03 — IMMUNOSTIMULANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Adjuvants, Immunologic
• Alcohols
• Amino Acids, Peptides, and Proteins
• Antineoplastic and Immunomodulating Agents
• Biological Factors
• Carbohydrates
• Colony-Stimulating Factors
• Compounds used in a research, industrial, or household setting
• Cytokines
• Ethylene Glycols
• Glycoconjugates
• Glycols
• Glycoproteins
• Granulocyte Colony-Stimulating Factors
• Hematinics
• Hematopoietic Cell Growth Factors
• Increased Myeloid Cell Production
• Intercellular Signaling Peptides and Proteins
• Leukocyte Growth Factor
• Macromolecular Substances
• Pegylated agents
• Peptides
• Polymers
• Proteins

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

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. [PubMed:21456630]
2. Curran MP, Goa KL: Pegfilgrastim. Drugs. 2002;62(8):1207-13; discussion 1214-5. doi: 10.2165/00003495-200262080-00012. [PubMed:12010086]
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. [PubMed:15078138]
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. [PubMed:25998211]
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. [PubMed:27789332]
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]

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

AHFS Codes

• 20:16.00 — Hematopoietic Agents

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	Malignant Solid Tumours	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	Unknown Status	Supportive Care	Breast Cancer / Neutropenia	1
3	Active Not Recruiting	Supportive Care	Chemotherapy Induced Neutropenia	2
3	Active Not Recruiting	Treatment	Breast Cancer	4

Pharmacoeconomics

Manufacturers

Not Available

Packagers

• Amgen Inc.
• Physicians Total Care Inc.

Dosage Forms

Form	Route	Strength
Solution	Subcutaneous
Injection	Subcutaneous	6 mg/0.6mL
Injection, solution	Cutaneous	6 MG
Kit	Subcutaneous	6 mg/0.6mL
Solution	Cutaneous; Intramuscular	6 MG
Injection, solution		6 mg/0.6mL
Solution	Subcutaneous	6 mg
Injection, solution	Subcutaneous	6 mg
Solution	Subcutaneous	10 mg
Injection, solution		10 mg/1mL
Solution
Injection, solution	Cutaneous; Intramuscular	6 MG
Injection, solution	Subcutaneous	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

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Patents

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

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Liquid

Experimental Properties

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

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Drug created on June 13, 2005 07:24 / Updated on October 27, 2020 11:13