Darbepoetin??Alfa

Publisher Website
Google Scholar
Abstract
Darbepoetin alfa (Aranesp®) is an analogue of recombinant human erythropoietin (rHuEPO) produced using recombinant DNA technology. The high number of sialic acid moieties in darbepoetin alfa results in a prolonged half-life and enhanced in vivo biological activity compared with rHuEPO (as demonstrated in animal studies) and permits a reduction in the frequency of administration. Subcutaneous darbepoetin alfa 2.25 μg/kg once weekly or 500μg once every 3 weeks (with a provision for dose adjustments) is an effective and well tolerated erythropoietic agent in anaemic patients with cancer receiving chemotherapy. In randomised, controlled clinical trials, the drug increased haemoglobin levels and reduced the need for blood transfusions in patients with various types of nonmyeloid malignancies and also ameliorated anaemia-related fatigue, thereby improving their health-related quality of life (HR-QOL) scores. The once-every-3-weeks dosage regimen provides further convenience by offering the possibility of synchronising its administration with most chemotherapy regimens. Direct comparisons between approved dosages of darbepoetin alfa and other erythropoietic agents have not been conducted. Such comparisons would be very helpful in formulating definitive conclusions about their relative efficacy and cost effectiveness. Darbepoetin alfa provides an effective and well tolerated treatment option for the treatment of anaemia in patients with cancer receiving chemotherapy. Darbepoetin alfa stimulates erythropoiesis by binding to surface receptors on red blood cell (RBC) precursors in the bone marrow and supporting their survival, differentiation and proliferation. Its high sialic acid content results in reduced affinity for the erythropoietin receptor, but a prolonged half-life with resultant enhanced in vivo biological activity compared with rHuEPO in murine models. Subcutaneous darbepoetin alfa was effective in stimulating erythropoiesis in vivo in a murine model of chemoradiotherapy-induced anaemia. Darbepoetin alfa is slowly absorbed after subcutaneous administration; it has a dose- and time-independent, predictable pharmacokinetic profile. Multiple-dose administration does not result in accumulation. Synchronous versus asynchronous darbepoetin alfa administration with chemotherapy results in increased maximum serum darbepoetin alfa concentration and area under the serum concentration-time curve values. In anaemic patients with cancer, the half-life of subcutaneous darbepoetin alfa (up to 88 hours) is generally longer than that reported for subcutaneous epoetin alfa (40 hours). Subcutaneous darbepoetin alfa has shown efficacy in the treatment of anaemia in patients with nonmyeloid malignancies receiving chemotherapy in several randomised trials of double-blind or nonblind design and in a noncomparative trial. The approved regimens of darbepoetin alfa involve starting dosages of 2.25 μg/kg once weekly or 500μg once every 3 weeks, with a provision for a 40% dose reduction if haemoglobin levels increase rapidly or exceed 11 g/dL. In two well designed trials, darbepoetin alfa 2.25 μg/kg once weekly significantly decreased the incidence of transfusion (weeks 5–13) while producing significantly greater haemoglobin and/or haematopoietic response rates compared with placebo in patients with lung cancer or lymphoproliferative malignancies. In addition, HR-QOL, as demonstrated by improvement in fatigue score associated with anaemia, was significantly improved in darbepoetin alfa recipients. Darbepoetin alfa 6.75 μg/kg once every 3 weeks for 12 weeks produced an approximately 3-fold higher haemoglobin response rate than placebo in a dose-finding study. The efficacy of darbepoetin alfa 6.75 μg/kg once every 3 weeks was similar when administered synchronously or asynchronously with a chemotherapy regimen given once every 3 weeks. Darbepoetin alfa 500μg once every 3 weeks was no less effective than darbepoetin alfa 2.25 μg/kg once weekly in terms of the proportion of patients requiring RBC transfusions after 15 weeks’ treatment in patients with nonmyeloid malignancies. HR-QOL results were also similar for the two treatment groups. Compared with placebo, darbepoetin alfa was also effective at a dosage of 300μg once every 3 weeks in decreasing the incidence of RBC transfusions in cancer patients with chemotherapy-induced anaemia in a well designed trial. These data were supported by the results of a large, single-arm trial (n = 1464) in which the majority of patients receiving darbepoetin alfa 300μg every 3 weeks for 13 weeks achieved a haemoglobin level of ≥11 g/dL and maintained it at 11–13 g/ dL. An early intervention (before the haemoglobin dropped below 10 g/dL) with this regimen was significantly more effective than a late intervention in achieving and maintaining a haemoglobin target level of 11–12 g/dL in a randomised trial in patients with chemotherapy-induced anaemia. Darbepoetin alfa once weekly or once every 3 weeks was generally well tolerated in patients with solid tumours or lymphoproliferative malignancies when administered subcutaneously at various different dosages in clinical trials of up to 6 months duration. Adverse events reported in clinical trials were generally in accordance with the underlying malignancy and chemotherapy. Fatigue, diarrhoea and oedema were the most frequent adverse events occurring in controlled clinical trials of darbepoetin alfa. Less frequent, but clinically significant, adverse events included hypertension, seizures/convulsions and thrombotic events, with death (unrelated to treatment) being the most common serious adverse event. Immunogenic reactions to darbepoetin alfa may occur, and although none of the clinical trials reported neutralising antibodies to darbepoetin alfa, there have been rare cases of pure red cell aplasia in patients treated with darbepoetin alfa in association with neutralising antibodies to erythropoietin.

This publication has 43 references indexed in Scilit: