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Lipegfilgrastim API Manufacturers & Suppliers

General Description:

Lipegfilgrastim, identified by CAS number 1117844-87-7, is a notable compound with significant therapeutic applications. 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 . It is used as an alternate to 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 . 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 . Lipegfilgrastim is a covalent conjugate of with a single methoxy polyethylene glycol (PEG) molecule via a carbohydrate linker consisting of glycine, N-acetylneuraminic acid and N-acetylgalactosamine . The average molecular mass of lipegfilgrastim comprises 18,798 Da for , 203 Da for GalNAc, 338 Da for glycylsialic acid and approximately 20,000 Da for PEG . 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 .

Indications:

This drug is primarily indicated for: 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) . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lipegfilgrastim undergoes metabolic processing primarily in: Lipegfilgrastim is metabolised via intra- or extracellular degradation by proteolytic enzymes . 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 . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lipegfilgrastim are crucial for its therapeutic efficacy: 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 . Based on its molecular weight, lipegfilgrastim is believed to be primarily absorbed via the lymphatic system then drained into the vascular system . 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lipegfilgrastim is an important consideration for its dosing schedule: The average terminal half-life ranged from approximately 32 to 62 hours after a single subcutaneous injection of 6 mg lipegfilgrastim in healthy individuals . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Lipegfilgrastim from the body primarily occurs through: Lipegfilgrastim undergoes two distinct clearance pathways: linear pathway composed of degradation by proteolytic enzymes and non-linear pathway involving neutrophil-mediated clearance . The elimination pathway by neutrophil-mediated clearance is saturated at higher doses . Lipegfilgrastim and its degraded fragments may undergo renal clearance . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lipegfilgrastim is distributed throughout the body with a volume of distribution of: Lipegfilgrastim has a weight-dependent volume of distribution of 70 mL/kg, indicating minimal distribution beyond the lymphatic or vascular system . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lipegfilgrastim is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lipegfilgrastim exerts its therapeutic effects through: 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 . Following a single subcutaneous dose administration of 100 μg/kg, lipegfilgrastim resulted in a significant increase in neutrophilic granulocyte and large unstained cell counts . G-CSF also increases the antibacterial activities of neutrophils including the phagocytosis . Due to structural similarity between lipegfilgrastim and pegfilgrastim, G-CSF receptor binding was equivalent between two molecules . However, lipegfilgrastim showed greater time-dependent resistance to neutrophil elastase degradation and greater retention of activity than pegfilgrastim . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lipegfilgrastim functions by: 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 . Subsequently, G-SCF stimulates the release of matured neutrophils from the bone marrow storage pools into the peripheral blood to enhance their function . 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 . This stimulatory effect of lipegfilgrastim may extend to other single lineage and multilineage progenitors and pluripotent haematopoietic stem cells . 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lipegfilgrastim belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Lipegfilgrastim is categorized under the following therapeutic classes: Adjuvants, Immunologic, Alcohols, Amino Acids, Peptides, and Proteins, Antineoplastic and Immunomodulating Agents, Biological Factors, Colony-Stimulating Factors, Cytokines, Ethylene Glycols, Glycols, Glycoproteins, Granulocyte Colony-Stimulating Factors, Hematopoietic Cell Growth Factors, Intercellular Signaling Peptides and Proteins, Macromolecular Substances, Pegylated agents, Peptides, Polymers, Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lipegfilgrastim include:

• Molecular Weight: 39000.0
• Molecular Formula: C866H1372N226O258S9*(C2H4O)n