Colony Stimulating Factors (Filgrastim / Pegfilgrastim)

Mechanism

Mechanism of Action

Filgrastim is a recombinant human granulocyte colony-stimulating factor of non-glycosylated polypeptide linear chain synthesized in modified cultures of *Escherichia coli*.

Cellular Mechanism of Neutrophilic Myelopoiesis

1. Recombinant G-CSF specifically binds to the G-CSFR receptor displayed on the surface of bone marrow myeloid precursors (myeloblasts, promyelocytes, myelocytes) and on peripheral mature neutrophils.
2. Binding stimulates receptor dimerization, recruiting the JAK-STAT tyrosine kinase cascade and inducing downstream signaling through the MAP kinase pathway.
3. This transcriptional cascade positively regulates myeloid transcription factors, favoring cell proliferation of granulocyte precursors, accelerating their maturation time from progenitor phase to mature segments from 14 days to only 1 - 2 days.
4. Stimulates the release of mature neutrophils from the vascular niches of the bone marrow into the systemic circulation and increases their bactericidal, phagocytic and peripheral chemotaxis functions.
5. Pegfilgrastim: It is a soluble conjugated form of filgrastim covalently linked to a 20 kDa polyethylene glycol (PEG) molecule. The PEG polymer masks enzymatic targets and prevents their glomerular clearance, markedly increasing their plasma retention time in vivo.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Subcutaneous, continuous intravenous or rapid intermittent infusion.
• Filgrastim: After subcutaneous injection, maximum concentrations are reached in 2 to 8 hours. Elimination half-life of 3 to 4 hours. Requires continuous daily subcutaneous injectable administration during the estimated period of neutropenia.
• Pegfilgrastim: Nonlinear self-adjusting clearance mediated predominantly by tissue uptake of mature neutrophils ("target receptor-mediated clearance"). At the beginning of the severe neutropenic phase, as there is no concentration of neutrophils, pegfilgrastim persists circulating in plasma with very long half-lives (~15-80 hours); As the bone marrow regenerates the mass of mature neutrophils, they capture and inactivate the drug, accelerating its physiological clearance. Allows a single subcutaneous dose per chemotherapy cycle.

Indicators and dose

Indications

• Reduction in the duration of severe neutropenia and the incidence of febrile neutropenia in patients with malignant neoplasms of myeloid or non-myeloid cell lineage treated with myelosuppressive cytotoxic chemotherapy.
• Mobilization of autologous or allogeneic peripheral blood progenitor cells (PBPC) for subsequent collection by apheresis and bone marrow transplantation.
• Treatment of severe hereditary or acquired chronic neutropenia with a severe recurrent course (cyclic neutropenia).
• Treatment of persistent neutropenia in HIV-infected patients with imminent clinical risk of major bacterial infections.

Dosage and Guides

• Filgrastim: Recommended dose of 0.5 MIU/kg (5 µg/kg) per day subcutaneously once a day. Continuous treatment should be maintained until the mature neutrophil count completely recovers, exceeding the absolute figure of 1,500/µL post-nadir.
• Pegfilgrastim: Recommended single dose of 6 mg subcutaneously per cycle of chemotherapy, administered mandatory at least 24 hours after completing the last chemotherapy infusion.

Pregnancy and Breastfeeding

FDA Category C. Data is limited. Use with extreme caution if the direct clinical benefit to the mother outweighs the potential fetal risk.

Security

Contraindications

Absolute

• Hypersensitivity to filgrastim, pegfilgrastim or proteins derived from *E. coli*.
• Acute myeloid neoplasms with peripheral circulating blasts > 10% (documented theoretical and clinical risk of accelerating leukemic myeloid neoplastic growth).
• Concomitant use within 24 hours before or after administration of active cytotoxic chemotherapy.

Relative

• History of persistent splenomegaly.
• Pre-existing sickle cell disease or sickle cell disease.

Adverse Effects (ADR)

• Osteomuscular Pain: Very common ADR, affecting up to 30-50% of patients. It is described as deep dull pain located in the pelvis, spine or ribs, secondary to the massive expansion of the intramedullary hematopoietic cellular tissue. Typically responds to minor analgesics or antihistamines (loratadine empirically).
• Splenomegaly and Splenic Rupture: Dilation of the spleen due to massive neutrophilic infiltration and vascular congestion. Cases of fatal splenic rupture have been reported after the use of G-CSF. Requires pain monitoring in the left hypochondrium.
• Acute Respiratory Distress Syndrome (ARDS): Due to massive neutrophilic inflammatory infiltration at the pulmonary alveolar level. It should be suspected if there is dyspnea or new interstitial infiltrates in the chest.
• Extreme transient leukocytosis: Peripheral leukocyte counts > 50,000/µL during the rapid peripheral regeneration phase.

Interactions

The administration of G-CSF is strictly contraindicated in the 24 hours before and after chemotherapy. Hematopoietic precursor cells in the phase of active proliferation induced by G-CSF are extremely sensitive to the cellular toxicity of cytotoxic chemotherapeutics, and may irreversibly aggravate bone marrow aplasia if they are administered simultaneously.