Alvograstim Mechanism of Action

Pharmacotherapeutic Group: Cytokines. ATC Code: L03AA02.
Pharmacology: Pharmacodynamics: Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Alvograstim containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within twenty-four hours, with minor increases in monocytes. In some SCN patients, filgrastim 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 in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within 1 to 2 days and to normal levels within 1 to 7 days.
Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. The incidence of fever and documented infections were not reduced in either setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
Use of filgrastim, either alone or after chemotherapy, mobilises haematopoietic progenitor cells into the peripheral blood. These autologous PBCPs 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 PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.
One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment-related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the results of nine prospective randomized trials, 8 retrospective studies and 1 case-controlled study, did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related mortality. (See Table 1.)

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Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation: In normal donors, a 10 µg/kg/day dose administered subcutaneously for 4 to 5 consecutive days allows a collection of ≥4 x 10⁶ CD34⁺ cells/kg recipient body weight in the majority of the donors after 2 leukaphereses.
Use of filgrastim in patients, children or adults, with SCN (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 filgrastim 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 filgrastim 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: Distribution: The volume of distribution in blood is approximately 150 ml/kg.
Elimination: Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The serum elimination half-life of filgrastim is approximately 3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with filgrastim 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.
Linearity/non-linearity: There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 mg/ml for 8 to 16 hrs.
Toxicology: Preclinical safety data: There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the monograph.