Filgrastim

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Pharmacology
Pharmacological action – leukopoietic.
Hematopoietic growth factor. It interacts with receptors on the surface of hematopoietic cells, stimulates cell proliferation, differentiation and functional activation. Human granulocytic colony stimulating factor (H-CSF) is produced by monocytes, fibroblasts and endothelial cells. H-CSF regulates neutrophil production and output of functionally active neutrophils from bone marrow to blood. H-CSF is not a specific factor only for neutrophils, studies in vivo and in vitro show its minimal direct impact on the production of other hematopoietic cells. In Phase I clinical trials with 96 patients with various non-myeloid malignant neoplasms it was shown that philgrastitis when administered in different ways – in/through (1-70 µg/kg 2 times per day), p/k (1-3 µg/kg once a day) or by prolonged p/k infusion (3-11 µg/kg/day) – dose-dependently increases the number of neutrophils with normal functional activity circulating in the blood (shown in chemotaxis and phagocytosis studies). After the end of the philgrastim therapy the number of leukocytes returned to the initial level in most cases within 4 days. An increase in lymphocyte counts against the background of philgrastim was recorded in healthy patients and in cancer patients. In clinical trials it was noted that the differential calculation of the number of leukocytes showed a shift of the formula to the left with the appearance of granulocytic precursor cells, including promyelocytes and myeloblasts. In addition, the appearance of Dohle bodies, increased granulocyte granulation and hypersegmentation of neutrophils were observed. These changes were transitory of fligrastim.

At the introduction of philgrastime in/in and p/k a positive linear dependence of its serum concentration on the dose was observed. The volume of distribution is approximately 150 ml/kg. Both after philgrastime administration and after philgrastime administration are eliminated from the body in accordance with 1st order kinetics. The average T1/2 value of serum filgrastima from both healthy and tumour patients is about 3.5 h; the clearance rate is about 0.5-0.7 ml/min/kg. With continuous 24-hour philgrastima infusions at a dose of 20 µg/kg for 11-20 days, an equilibrium concentration is achieved in the blood without signs of cumulation during the observed period.

Application of Filgrastim substance
Neutropenia (including in patients receiving cytostatic drugs due to non-myeloid malignancies); reduction of neutropenia period and its clinical consequences in patients preparing for bone marrow transplantation; persistent neutropenia in patients with advanced stage of HIV infection (absolute neutrophil number 1000 cells/μL and less); peripheral stem cell mobilization (in tonnes of neutropenia).after myelosuppressive therapy); neutropenia (hereditary, periodic or idiopathic – neutrophil number is lower or equal to 500 cells/µl) and severe or recurrent infections (in history) during the last 12 months.

Contraindications .
Hypersensitivity, severe congenital neutropenia in abnormal cytogenetics (Costmann’s syndrome), increased doses of cytotoxic chemotherapeutic agents above the recommended ones, hepatic and/or renal failure, age up to 1 year.

Restrictions on use
Malignant and pre-tumor diseases of myeloid nature, combination with high-dose therapy.

Use in pregnancy and breastfeeding
During pregnancy it is possible if the expected effect of therapy exceeds the potential risk to the fetus (no adequate and strictly controlled trials have been conducted, safety for pregnant women has not been established).

Studies on rabbits have shown that filgrastimum causes side effects in pregnant rabbits when taken at doses 2-10 times higher than the human dose. When filgrastim was administered to rabbits at doses of 80 µg/kg/day, an increased rate of miscarriage and embryo mortality was observed. Filgrastim administered to pregnant rabbits at doses of 80 µg/kg/day during organogenesis resulted in urogenital bleeding, reduced food intake, increased foetal resorption, abnormal development, reduced body weight, number of viable cubs. External anomalies were not observed in fetuses of females who received doses of 80 µg/kg/day.

Studies in pregnant rats with daily injections during organogenesis at doses up to 575 µg/kg/day showed no signs of lethality, teratogenicity or behavioural effects in the offspring.

Fetal action category by FDA is C.

Not recommended for breastfeeding mothers (it is not known if filgrastime penetrates breast milk).

Side effects of the substance Filgrastima
Oncological patients receiving myelosuppressive chemotherapy.

In clinical studies involving more than 350 patients who received philgrastime after cytotoxic chemotherapy, most side effects were a complication of a major malignant disease.https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103353

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