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Neutrophil recovery after bone
Neulasta (PEGylated Approved Neutropenia Amgen
GM-CSF In clinical trials Immune stimulation in malignant Berlex
GM-CSF In clinical trials Myeloid reconstitution following Cangene
stem cell transplantation
Table 6.5. Some causes of neutropenia
Genetic (particularly in black populations)
Severe bacterial infection Severe sepsis Severe viral infection Aplastic anaemia*
Hodgkin’s/non-Hodgkin’s lymphoma Various drugs, especially anti-cancer drugs Autoimmune neutropenia
*Aplastic anaemia describes bone marrow failure characterized by serious reduction in the number of stem cells present
is a condition characterized by a decrease in blood neutrophil count below (normal blood count 2.0-7.5x109 cells/l). Its clinical symptoms include the frequent and usually serious infections, often requiring hospitalization. Neutropenia may be caused by a number of factors (Table 6.5), at least some of which are responsive to CSF treatment. Particularly noteworthy is neutropenia triggered by administration of chemotherapeutic drugs to cancer patients. Chemotherapeutic agents (e.g. cyclophosphamide, doxorubicin and methotrexate), when administered at therapeutically effective doses, often induce the destruction of stem cells and/or compromise stem cell differentiation.
Filgrastim is a recombinant human G-CSF (produced in E. coli), approved for chemotherapy-induced neutropenia since 1991. Although the 18.8 kDa recombinant product is not glycosylated and contains an additional N-terminal methionine residue (due to expression in E. coli), it displays biological activity indistinguishable from native G-CSF. The product is presented in freeze-dried format and contains buffer elements as well as sorbitol and Tween as excipients.
Administration of filgrastim (0.5 mg/kg/day) to healthy volunteers for six consecutive days resulted in up to a 10-fold increase in their absolute neutrophil count. Daily administration to patients receiving chemotherapy greatly reduced the duration and severity of leucopenia (reduction in the numbers of total white blood cells). The magnitude of the specific neutrophil response depended upon the number of progenitor cells still surviving upon commencement of treatment. Neutrophils from patients with neutropenia treated with filgrastim also display enhanced phagocytosis and chemotaxis, at least transiently.
Filgrastim is used in conjunction with cancer chemotherapy in one of two ways: prophylactic administration aims to prevent onset of neutropenia in the first place, while therapeutic administration aims to reverse neutropenia already established. It is generally effective in both circumstances and in clinical trials it was found to reduce the number of (neutropenia-induced) days of patient hospitalization by up to 50%. Filgrastim administration may also permit modest increases in the maximum dose intensity utilizable in chemotherapeutic regimes.
Filgrastim is usually administered by subcutaneous injection. Dosage levels range from 5-10 mg/kg/day, with peak plasma drug concentrations being observed 2-8 hours after administration. The mechanism by which filgrastim is removed from circulation is unclear, but the drug’s elimination half-life ranges from less than 2h to almost 5h. The drug is generally well tolerated. The most common adverse reaction is mild bone pain, which occurs in up to 20% of cancer patients receiving treatment. This is easily treated with analgesics.
Neutropenia 1.5x109 cells/l occurrence of
HAEMOPOIETIC GROWTH FACTORS 263
While filgrastim has proved a useful adjuvant to chemotherapy for many cancers, its administration in cases of myeloid leukaemia would give cause for concern, as these cells express receptors for G-CSF. In such cases, G-CSF could potentially promote accelerated growth of these malignant cells.
Filgrastim also shows therapeutic promise in the treatment of additional conditions characterized by depressed blood neutrophil counts. Such conditions include severe chronic neutropenia, leukaemia and AIDS.
Neulasta is the tradename given to a PEGylated form of filgrastim approved for general medical use in the USA in 2002. Manufacture of this product entails covalent attachment of an activated monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of filgrastim. The product is formulated in the presence of acetate buffer, sorbitol and polysorbate and is presented in pre-filled syringes for subcutaneous injection. As in the case of PEGylated interferons (IFNs) (Chapter 4), the rationale for PEGylation is to increase the drug’s plasma half-life, thereby reducing the frequency of injections required.