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Filgrastim

A Review of its Pharmacological Properties and Therapeutic Efficacy in Neutropenia

  • Drug Evaluation
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Summary

Synopsis

Filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), has identical biological activity to that of endogenous human G-CSF, but differs in that it contains an N-terminal methionine residue and is not glycosylated. It principally stimulates activation, proliferation and differentiation of neutrophil progenitor cells and has been evaluated in the treatment of patients with various neutropenic conditions, both iatrogenic and disease-related.

Two comparative studies have demonstrated that prophylactic administration of filgrastim 230 μg/m2/day significantly reduces the incidence, duration and severity of neutropenia in patients with previously untreated small-cell lung cancer receiving standard-dose chemotherapy with CDE (cyclophosphamide, doxorubicin plus etoposide). Concomitant with the amelioration of neutropenia, the incidence of febrile neutropenia was significantly reduced by 50% and there were 35 and 50% decreases in hospitalisation rates and intravenous antibiotic requirements.

Since not all patients receiving standard-dose chemotherapy are at risk of infectious complications, prophylactic filgrastim use may be reserved for those patients who have developed febrile neutropenia during a previous cycle of the same regimen. This strategy may prove less costly, although potential savings must be weighed against a greater risk of patient morbidity and reduced quality of life. When combined with standard intravenous antibiotic therapy, filgrastim further decreases morbidity in patients with established febrile neutropenia and may have a positive impact on overall treatment costs by shortening the length of hospitalisation.

Attention is focused on the use of haematopoietic growth factors to support dose-intensification of chemotherapy with a view to improving treatment outcomes in patients with chemo-responsive tumours. Filgrastim, used alone, permits modest increases in dose-intensity and/or dose-escalation of some standard-dose chemotherapy regimens. Moreover, the drug has proven useful as an adjunct to myeloablative chemotherapy followed by stem cell rescue with autologous bone marrow transplantation and/or peripheral blood progenitor cells. However, the impact of these dose-intensification approaches on survival remains to be determined in well-controlled clinical studies.

Filgrastim is effective in increasing the neutrophil count and decreasing morbidity in patients with severe chronic neutropenia, including Kostmann’s syndrome, and in idiopathic and cyclic neutropenia. In addition, filgrastim has accelerated neutrophil recovery in patients with idiosyncratic drug-induced agranulocytosis.

Available data indicate that filgrastim is generally well tolerated. The most frequent adverse reaction is mild to moderate medullary bone pain, reported by approximately 20% of patients, although this can generally be controlled using simple analgesics without the need to discontinue treatment.

In summary, filgrastim should be regarded as a first-line therapy in patients with severe chronic neutropenia and, when used judiciously, a valuable adjuvant to cytotoxic cancer chemotherapy in patients with nonmyelogenous malignancies. Further clinical experience should help define a wider role for the drug in the treatment and management of other conditions associated with neutropenia, including acquired immunodeficiency syndrome.

Pharmacological Properties

Filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) is a haematopoietic growth factor which acts primarily to stimulate proliferation and differentiation of committed progenitor cells of the granulocyte-neutrophil lineage into functionally mature neutrophils. The neutrophilia induced by filgrastim is characterised by a dose-dependent ‘left-shift’ towards progenitor cells; mature neutrophils show normal or enhanced function in vitro after exposure to filgrastim.

Filgrastim causes a transient decrease in the absolute neutrophil count (ANC) within the first hour after administration, followed by a rapid increase within 4 to 5 hours. The increase in ANC was 2- to 12-fold over pretreatment values after subcutaneous administration of filgrastim 1 to 60 μg/kg and was dose-proportional. Neutrophil levels decrease exponentially to normal levels generally within 2 days of the last dose.

In cancer patients receiving chemotherapy, administration of filgrastim shortened the time to occurrence of the neutrophil nadir and dose-proportionally decreased the duration and severity of neutropenia. However, the neutrophil response to conventional dosages of filgrastim may vary, depending on the previous level of chemotherapy or radiotherapy.

Filgrastim 1 to 60 μg/kg does not affect eosinophil or basophil counts but causes a minor dose-dependent increase in monocyte levels at higher doses (10 to 60 μg/kg). Minor increases in lymphocytes may also occur at high doses, probably by an indirect mechanism.

Peak plasma concentrations of filgrastim are dose-proportional and occurred 2 to 8 hours after subcutaneous administration in children with severe chronic neutropenia. Filgrastim clearance appears to be dependent on the neutrophil count; clearance increased from 0.024 to 0.044 L/h (0.40 to 0.74 ml/min) over 14 days as the ANC increased in children with severe chronic neutropenia. Similarly, the elimination half-life decreased from 4.7 to <2 hours as the ANC increased. The mechanism by which filgrastim is metabolised and excreted is not known.

Therapeutic Efficacy

Filgrastim has been widely evaluated as an adjunct to chemotherapy in the treatment of nonmyelogenous cancers, although its use in myelodysplastic syndromes and leukaemia should be regarded as experimental pending the availability of further clinical data.

In 2 placebo-controlled studies, prophylactic administration of filgrastim 230 μg/m2/day for up to 14 days significantly reduced the incidence, severity and duration of neutropenia in patients with previously untreated small-cell lung cancer receiving standard-dose chemotherapy with CDE (cyclophosphamide, doxorubicin plus etoposide). As a result, there was a significant 50% reduction in the incidence of febrile neutropenia and this was associated with 35 and 50% decreases in the use of measured healthcare resources (hospitalisations and intravenous antibiotic requirements). In other randomised studies, filgrastim further reduced morbidity when combined with prophylactic antimicrobial and antifungal therapy and standard antibiotic treatment in patients with established febrile neutropenia.

Various pharmacoeconomic analyses of filgrastim therapy have been reported. Generally, these show that the cost of providing prophylactic filgrastim therapy can at least be partially recouped through savings in hospitalisation costs. However, careful patient selection is required to maximise the potential cost-benefits associated with prophylactic filgrastim use. In contrast, therapeutic administration to patients with febrile neutropenia receiving standard antibiotic treatment has reduced overall treatment costs by 40% compared with placebo, although further studies are required to confirm this promising result.

When administered to patients receiving high-dose chemotherapy followed by bone marrow transplantation (BMT), filgrastim accelerates the recovery of adequate neutrophil levels. Compared with historical controls, filgrastim tends to reduce the severity and duration of infection-related complications in patients receiving autologous bone marrow transplantation (ABMT), reflected in fewer days with febrile neutropenia as well as significant reductions in antibiotic use and hospitalisation times. However, significant effects have varied between different centres and confirmation of the clinical benefits of filgrastim is required in detailed reports of randomised studies.

The use of peripheral blood progenitor cells (PBPCs) administered in conjunction with, or even as an alternative to, BMT is now being investigated. Data from nonrandomised studies indicate that PBPC infusion accelerates haematopoietic reconstitution after high-dose chemotherapy and ABMT, with significant reductions in hospital stay, antibiotic use and transfusion requirements. Mobilisation of PBPCs with filgrastim has been successfully integrated into induction- or salvage-chemotherapy regimens, although the response may vary depending on the previous level of chemotherapy.

Filgrastim 3.4 to 11.5 μg/kg/day was effective in reducing the incidence and duration of infection in patients with severe chronic neutropenia, including idiopathic, cyclic and congenital neutropenias. An increase in ANC to >1.5 × 109/L was seen in 90% of patients. The data available suggest that filgrastim is more effective than granulocyte-macrophage colony-stimulating factor in these patients.

Preliminary findings suggest that coadministration of filgrastim with the antiviral drugs zidovudine or ganciclovir is effective in attenuating the leucopenia associated with these agents, thus permitting continued therapy in disorders such as acquired immunodeficiency syndrome (AIDS). Filgrastim may also be useful in accelerating neutrophil recovery in patients with idiosyncratic drug-induced agranulocytosis.

Tolerability

Filgrastim is generally well tolerated. The most common adverse reaction is mild to moderate medullary bone pain, which is normally controlled by simple analgesics and generally resolves on continued treatment. In placebo-controlled trials, bone pain occurred in 20% of patients with cancer receiving chemotherapy and filgrastim.

Minor increases in plasma levels of leucocyte alkaline phosphatase, lactate dehydrogenase and uric acid are frequent with filgrastim, and are possibly related to the increase in neutrophils. Asymptomatic splenomegaly occurs in about 25% of patients receiving long term treatment with filgrastim for severe chronic neutropenia.

Rare adverse events occurring during filgrastim therapy include vasculitis, acute neutrophilic dermatosis and possible anaphylactoid reactions. Filgrastim has not been reported to cause increased eosinophil levels. G-CSF has rarely been reported to cause capillary leak syndrome.

Dosage and Administration

Filgrastim can be administered by subcutaneous injection or infusion, or intravenous infusion. The subcutaneous route allows the drug to be administered on an outpatient basis where this is appropriate. An initial starting dose of 5 μg/kg/day is recommended for the treatment of chemotherapy-induced neutropenia and idiopathic and cyclic neutropenias. A higher starting dose of 10 μg/kg/day is recommended in patients receiving high-dose chemotherapy followed by bone marrow transplant, and in patients with congenital neutropenias such as Kostmann’s syndrome.

Caution should be exercised when administering filgrastim to patients with myeloid malignancies or myelodysplastic syndromes because of the possibility of filgrastim promoting tumour growth or progression to malignancy.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    James E. Frampton, C. Rhoda Lee & Diana Faulds

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Various sections of the manuscript reviewed by: W.M. Bennett, Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland, Oregon, USA; L.A. Boxer, Department of Pediatrics, C.S. Mott Children’s Hospital, Ann Arbor, Michigan, USA; D.C. Dale, Department of Medicine, University of Washington, Seattle, Washington, USA; D. Dunlop, CRC Department of Medical Oncology, University of Glasgow, Glasgow, Scotland; K. Eguchi, Department of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; W.E. Evans, Pharmaceutical Department, St Jude Children’s Research Hospital, Memphis, Tennessee, USA; R. Haas, Universität Heidelberg, Heidelberg, Germany; Y. Itoh, The First Department of Internal Medicine, Tokyo Medical College, Tokyo, Japan; D.C. Lynch, Department of Haematology, University College London Medical School, London, England; E. Masson, Pharmaceutical Department, St Jude Children’s Research Hospital, Memphis, Tennessee, USA; R. Pettengell, Developmental Hematopoiesis Laboratory, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.

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Frampton, J.E., Lee, C.R. & Faulds, D. Filgrastim. Drugs 48, 731–760 (1994). https://doi.org/10.2165/00003495-199448050-00007

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