Neupogen Mechanism of Action





Zuellig Pharma
Full Prescribing Info
Pharmacology: Pharmacodynamics: Mechanism of Action: Human granulocyte-colony stimulating factor is a glycoprotein, which regulates the production and release of functional neutrophils from the bone marrow. Neupogen containing r-metHuG-CSF (filgrastim), causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some severe chronic neutropenia patients Neupogen can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment.
Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced by the human body in response to Neupogen show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of Neupogen therapy, circulating neutrophil counts decrease by 50% within one to two days, and to normal levels within one to seven days.
Treatment with Neupogen in patients undergoing cytotoxic chemotherapy or myeloablative therapy followed by bone marrow transplantation leads to a significant reduction in the incidence, severity and duration of neutropenia and febrile neutropenia, and consequently, fewer admissions to the hospital, shorter duration of hospitalisation and less antibiotics as compared to patients on cytotoxic chemotherapy alone.
Treatment with Neupogen significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia. The incidence of fever and documented infections was not reduced in this setting.
Use of Neupogen, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into the peripheral blood. These autologous peripheral blood progenitor cells (PBPC) may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.
Recipients of allogeneic peripheral blood progenitor cells mobilised with Neupogen experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.
Use of Neupogen in patients, children or adults, with severe chronic neutropenia (severe congenital, cyclic and idiopathic neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a reduction of infection and related events. Use of Neupogen in patients with HIV infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with HIV infection treated with Neupogen show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
Pharmacokinetics: Absorption: After s.c. administration, filgrastim is rapidly absorbed, and peak serum concentrations are attained 2 to 8 hours after dosing. Elimination half-life after i.v. and s.c. dosing is usually between 2 and 4 hours. Clearance and half-life are dependent on dose and neutrophil count. When neutrophil-mediated clearance is saturated by high filgrastim concentrations or is diminished by neutropenia, the linear clearance pathway predominates and the pharmacokinetics appear linear. The absolute bioavailability of filgrastim after s.c. administration is estimated to be 62% for a 375 μg dose and 72% for a 750 μg dose. After discontinuation of dosing, filgrastim concentrations decrease to endogenous concentrations within 24 hours.
A decrease in filgrastim serum concentrations is evidenced upon multiple dosing in healthy subjects and in cancer subjects before chemotherapy. This increase in clearance of filgrastim is dose dependent, and the magnitude of increase appears closely related to the degree of neutrophilia in the recipients, which is consistent with increased neutrophil-mediated clearance by the expanded neutrophil pool. In subjects receiving filgrastim after chemotherapy, plateau serum concentrations are maintained until onset of haematopoietic recovery.
Distribution: There is a positive linear correlation between the dose and the serum concentration of Neupogen, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 ng/ml for 8 to 16 hours. The volume of distribution in blood is approximately 150 ml/kg.
Elimination: Continuous infusion with Neupogen over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives.
Clearance of Neupogen has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The mean serum elimination half-life of Neupogen is approximately 3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg.
Pharmacokinetics in Special Populations: Paediatrics: The pharmacokinetics of filgrastim in paediatric patients after chemotherapy is similar to those in adults receiving the same weight-normalised doses, suggesting no age-related differences in the pharmacokinetics of filgrastim.
Geriatrics: Pharmacokinetic data in geriatric patients (> 65 years) are not available.
Renal or hepatic Impairment: Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. Dose adjustment is not required in these circumstances. A trend towards higher systemic exposure to filgrastim is observed in patients with ESRD compared with healthy subjects and subjects with creatinine clearance of 30-60 ml/min.
Toxicology: Preclinical Safety: Carcinogenicity: The carcinogenic potential of filgrastim has not been studied. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolising enzyme system.
Certain malignant cells have been shown to express granulocyte-colony stimulating factor (G-CSF) receptors. The possibility that filgrastim can act as growth factor for any tumor type cannot be excluded.
Impairment of Fertility: Filgrastim had no observed effect on the fertility of male or female rats, or gestation, at doses up to 500 μg/kg.
Teratogenicity: There is no evidence from studies in rats and rabbits that Neupogen is teratogenic. An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been seen.
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