Identification

Name
Lipegfilgrastim
Accession Number
DB13200
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Lipegfilgrastim, previously known as XM22, is a pegylated, recombinant granulocyte colony-stimulating factor (G-CSF) that was synthetized using a highly site-specific glycoPEGylation technology [2]. It is used as an alternate to Pegfilgrastim for prophylactic use in cancer patients receiving chemotherapy and at risk for developing chemotherapy-induced neutropenia. Since July 2013, lipegfilgrastim is marketed by the EMA as Lonquex for subcutaneously injection, where it is administered once following cytotoxic chemotherapy for each chemotherapy cycle in adult patients being treated with cytotoxic chemotherapy for malignancy. It aims to reduce the duration of neutropenia and the incidence of febrile neutropenia.

Neutropenia and febrile neutropenia (FN) are frequent and potentially fatal complications that occur from myelosuppressive anticancer treatments [2]. Severe chemotherapy-induced neutropenia and febrile neutropenia significantly increases the risk for life-threatening infection and sepsis. Granulocyte colony-stimulating factors (G-CSFs) were introduced in the 1980's to the clinical setting to stimulate neutrophil proliferation and differentiation, thereby reducing the duration and severity of chemotherapy-induced neutropenia [2]. Lipegfilgrastim is a covalent conjugate of Filgrastim with a single methoxy polyethylene glycol (PEG) molecule via a carbohydrate linker consisting of glycine, N-acetylneuraminic acid and N-acetylgalactosamine [5]. The average molecular mass of lipegfilgrastim comprises 18,798 Da for Filgrastim, 203 Da for GalNAc, 338 Da for glycylsialic acid and approximately 20,000 Da for PEG [6]. PEG moiety protects the active molecule from enzyme degradation, which allows longer half-life of drug and less frequent dosing-schedule in addition to acceptable safety and efficacy profile [2].

Protein structure
Db13200
Protein chemical formula
C866H1372N226O258S9*(C2H4O)n
Protein average weight
39000.0 Da (glycoPEGylated, approximate)
Sequences
>Lipegfilgrastim sequence
MTPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLCATYKLCHPEELVLLGHSLGIPWA
PLSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQ
QMEELGMAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFLEVSYRVLRHLAQP
Download FASTA Format
Synonyms
Not Available
External IDs
XM-22 / XM22
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LonquexInjection, solution6 mgSubcutaneousSicor Biotech Uab2013-07-25Not applicableEu
LonquexInjection, solution6 mgSubcutaneousSicor Biotech Uab2013-07-25Not applicableEu
Categories
UNII
4AWF0N6QV3
CAS number
1117844-87-7

Pharmacology

Indication

Indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) [5].

Associated Conditions
Pharmacodynamics

Mimicking endogenous granulocyte colony-stimulating factors, lipegfilgrastim enhances the number and function of circulating neutrophils by binding to endogenous G-CSF receptors. A small increase in monocyte and/or lymphocyte counts may also be observed [5]. Following a single subcutaneous dose administration of 100 μg/kg, lipegfilgrastim resulted in a significant increase in neutrophilic granulocyte and large unstained cell counts [6]. G-CSF also increases the antibacterial activities of neutrophils including the phagocytosis [5]. Due to structural similarity between lipegfilgrastim and pegfilgrastim, G-CSF receptor binding was equivalent between two molecules [2]. However, lipegfilgrastim showed greater time-dependent resistance to neutrophil elastase degradation and greater retention of activity than pegfilgrastim [2].

Mechanism of action

Endogenous granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates neutrophil progenitors. It is produced mainly by monocytes, fibroblasts and endothelial cells to promote the development of neutrophils and increase their proliferation and maturation [4]. Subsequently, G-SCF stimulates the release of matured neutrophils from the bone marrow storage pools into the peripheral blood to enhance their function [5, 4]. Via binding to to the human G-CSF receptors, lipegfilgrastim activates the receptor signalling pathway as a growth factor to stimulate proliferation of haematopoietic progenitor cells and their differentiation into mature cells, and promote subsequent release into the peripheral blood [5]. This stimulatory effect of lipegfilgrastim may extend to other single lineage and multilineage progenitors and pluripotent haematopoietic stem cells [5]. The presence of the PEG moiety in lipegfilgrastim decreases the plasma clearance and extends the drug's terminal elimination half-life, allowing for less frequent dosing [1].

TargetActionsOrganism
AGranulocyte colony-stimulating factor receptor
agonist
Human
Absorption

In studies of healthy volunteers receiving a single subcutaneous injection of 6 mg of lipegfilgrastim, the peak plasma concentration of lipegfilgrastim was reached after a median of 30 to 36 hours [5]. Based on its molecular weight, lipegfilgrastim is believed to be primarily absorbed via the lymphatic system then drained into the vascular system [7]. Peak concentration and area under the curve, indicating full bioavailability, was lower in injection site of the thigh compared to subcutaneous injection in the abdomen and in the upper arm, with differences among the injection sites being the greatest in males compared to female subjects [5].

Volume of distribution

Lipegfilgrastim has a weight-dependent volume of distribution of 70 mL/kg, indicating minimal distribution beyond the lymphatic or vascular system [7].

Protein binding
Not Available
Metabolism

Lipegfilgrastim is metabolised via intra- or extracellular degradation by proteolytic enzymes [5]. Following binding to the G-CSF receptors, it is proposed to be internalized by neutrophils via a non-linear process, and then undergoes degradation within the cell by endogenous proteolytic enzymes. Alternatively, the linear pathway is likely due to extracellular protein degradation by neutrophil elastase and other plasma proteases [5].

Route of elimination

Lipegfilgrastim undergoes two distinct clearance pathways: linear pathway composed of degradation by proteolytic enzymes and non-linear pathway involving neutrophil-mediated clearance [7]. The elimination pathway by neutrophil-mediated clearance is saturated at higher doses [3]. Lipegfilgrastim and its degraded fragments may undergo renal clearance [5].

Half life

The average terminal half-life ranged from approximately 32 to 62 hours after a single subcutaneous injection of 6 mg lipegfilgrastim in healthy individuals [5].

Clearance

In a phase 1, multinational, open-label, single-arm study of paediatric patients with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy, the mean apparent clearance (CL/F) was approximately 71 mL/h, 120 mL/h, and 116 mL/h for age groups of 2-6 years, 6-12 years, and 12-18 years, respectively [3].

Toxicity

In safety pharmacological studies in rats and dogs, lipegfilgrastim was well tolerated at a single subcutaneous dose of 10 mg/kg. In the renal excretion study in rats, an intravenous dose of 250 μg/kg was well tolerated [6]. While mutagenicity and genotoxicity studies have not been conducted with lipegfilgrastim, G-CSF has been reported to stimulate tumour growth and intratumoural vessel density in animal tumour models [6].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-deoxyglucose2-deoxyglucose may increase the myelosuppressive activities of Lipegfilgrastim.
8-azaguanine8-azaguanine may increase the myelosuppressive activities of Lipegfilgrastim.
AcipimoxAcipimox may increase the myelosuppressive activities of Lipegfilgrastim.
AldesleukinAldesleukin may increase the myelosuppressive activities of Lipegfilgrastim.
AlemtuzumabAlemtuzumab may increase the myelosuppressive activities of Lipegfilgrastim.
AllicinAllicin may increase the myelosuppressive activities of Lipegfilgrastim.
AllopurinolAllopurinol may increase the myelosuppressive activities of Lipegfilgrastim.
AltretamineAltretamine may increase the myelosuppressive activities of Lipegfilgrastim.
AmsacrineAmsacrine may increase the myelosuppressive activities of Lipegfilgrastim.
AnacetrapibAnacetrapib may increase the myelosuppressive activities of Lipegfilgrastim.
Food Interactions
Not Available

References

General References
  1. Buchner A, Lammerich A, Abdolzade-Bavil A, Muller U, Bias P: Lipegfilgrastim: pharmacodynamics and pharmacokinetics for body-weight-adjusted and 6 mg fixed doses in two randomized studies in healthy volunteers. Curr Med Res Opin. 2014 Dec;30(12):2523-33. doi: 10.1185/03007995.2014.962131. Epub 2014 Sep 25. [PubMed:25251999]
  2. Guariglia R, Martorelli MC, Lerose R, Telesca D, Milella MR, Musto P: Lipegfilgrastim in the management of chemotherapy-induced neutropenia of cancer patients. Biologics. 2016 Jan 22;10:1-8. doi: 10.2147/BTT.S58597. eCollection 2016. [PubMed:26858523]
  3. Belogurova MB, Kizyma ZP, Garami M, Csoka M, Lamson MJ, Buchner A, Bias P, Lammerich A: A pharmacokinetic study of lipegfilgrastim in children with Ewing family of tumors or rhabdomyosarcoma. Cancer Chemother Pharmacol. 2017 Jan;79(1):155-164. doi: 10.1007/s00280-016-3216-2. Epub 2016 Dec 16. [PubMed:27986986]
  4. 25. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 315). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
  5. European Medicines Agency (EMA) Summary of Product Characteristics: Lonquex (lipegfilgrastim) [Link]
  6. Australian Public Assessment Report for Lipefilgrastim (rbe) [Link]
  7. Therapeutic Goods Administration (TGA) product Information: Lonquex [Link]
External Links
Not Available
ATC Codes
L03AA14 — Lipegfilgrastim
MSDS
Download (20.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailablePharmacodynamics / Pharmacokinetics1
1CompletedSupportive CareEwing Family of Tumors, Rhabdomyosarcoma1
1, 2RecruitingTreatmentMalignant Lymphomas / Multiple Myeloma (MM)1
3CompletedTreatmentAggressive B Cell Non-Hodgkin Lymphomas at High Risk for R-CHOP-21-induced Neutropenia1
Not AvailableCompletedNot AvailableCancer, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous6 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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

Drug created on June 23, 2017 14:37 / Updated on August 02, 2018 06:48