Administration Of Darbepoetin Alfa Research Articles

Once-Monthly Administration of Darbepoetin Alfa for the Treatment of Patients with Chronic Heart Failure and Anemia

In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin<or=12.5 g/dL) in 2 randomized, double-blind, placebo-controlled studies. Subcutaneous (SC) and intravenous administration of 0.75 microg/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 microg/kg SC doses with placebo. Darbepoetin alfa (0.75 microg/kg SC) pharmacokinetics were similar in CHF patients and healthy subjects, with a mean (+/-SD) bioavailability of 29 (+/-11)% and 37 (+/-8)%, respectively. In anemic CHF patients, mean (+/-SD) increases in hemoglobin at 4 weeks after the second monthly dose of 2.0, 3.0, and 5.0 microg/kg (SC) of darbepoetin alfa were 2.3 (+/-0.6), 1.4 (+/-1.0), and 2.4 (+/-1.9) g/dL, respectively. Darbepoetin alfa 0.75 microg/kg (SC) given twice, 1 month apart, was insufficient to increase hemoglobin in this study. No severe, drug-related adverse events occurred. Darbepoetin alfa administered once monthly elevates and maintains the hemoglobin concentration in patients with CHF and anemia.

O-060 Routine once-weekly darbepoetin alfa administration is cost-effective in lung cancer patients with chemotherapy-induced anemia: A Markov analysis

O-060 Routine once-weekly darbepoetin alfa administration is cost-effective in lung cancer patients with chemotherapy-induced anemia: A Markov analysis

Evaluating the effectiveness of darbepoetin alfa 300 mcg Q3W for the treatment of chemotherapy-induced anemia

8129 Background: Darbepoetin alfa (DA) 200 mcg Q2W has been shown to be as effective as epoetin alfa (EA) 40000 U QW for the treatment of chemotherapy-induced anemia (CIA; Schwartzberg 2004). In this controlled study, 82% of pts treated with DA 200 mcg Q2W achieved the target Hb (≥ 11g/dL) in a median time of 5 weeks (wks), compared with 86% of pts treated with EA in a median time of 4 wks. In addition, 16% of pts treated with DA and 17% treated with EA required transfusions. Administration of DA Q3W could offer the possibility to synchronize anemia therapy with chemotherapy. Methods: This 16-wk, single-arm, open-label study is designed to assess the effectiveness of DA 300 mcg Q3W in achieving and maintaining a target Hb consistent with evidence-based guidelines (11–12g/dL) in patients (pts) with CIA. Secondary endpoints include transfusion incidence, change in Hb from baseline (BL) and Pt-reported outcomes (assessed by the FACT-F). DA could be increased after 6 wks (2 doses) based on pt response. At any time, DA could be withheld or reduced if Hb increased rapidly or Hb threshold was reached. This interim analysis includes 634 pts enrolled before 14 Jun 2004 who completed 16 wks of treatment and is stratified by BL Hb of <10 and ≥10g/dL. Results: Most pts were female (61%) and white (81%) with a median age of 64 yrs. The most common tumors were lung (24%) and breast (22%). The majority of pts, regardless of BL Hb, achieved and maintained target Hb (Table). For pts with BL Hb < 10g/dL, substantial increases in Hb and FACT-F scores were observed. Safety results were consistent with those described for other DA studies. Conclusions: DA 300 mcg Q3W is well-tolerated and effective for achieving and maintaining evidence-based target Hb levels in pts with CIA, allowing the opportunity to synchronize the administration of DA with common chemotherapy regimens. Baseline Hb < 10 g/dL (n = 192) Baseline Hb = 10 g/dL (n = 411) Overall (n = 634) Mean (SD) baseline Hb 9.3 g/dL (0.5) 10.6 g/dL (0.3) 10.2 g/dL (0.7) (n = 603) % (95% CL) of pts achieving Hb target (K-M method) 79% (72, 86) 91% (88, 94) 88% (85, 91) (n = 633) Median (Q1, Q3) time to Hb target (K-M method) 9 weeks (4, 16) 3 weeks (2, 7) 4 weeks (2, 11) Mean (95% CL) Hb after achieving target Hb level 11.5 g/dL (11.4, 11.7) (n = 130) 11.5 g/dL(11.5, 11.6) (n = 353) 11.5 g/dL (11.5, 11.6) (n = 507) Mean (95% CL) change in Hb from baseline at week 16 (LVCF approach) 1.6 g/dL (1.3, 1.8) 0.8 g/dL (0.7, 1.0) 1.1 g/dL (0.9, 1.2) (n = 603) Mean (95% CL) change in Hb from baseline at week 16 (availble data approach) 2.2 g/dL (1.9, 2.5) (n = 123) 1.1 g/dL (0.9, 1.3) (n = 289) 1.4 g/dL (1.3, 1.6) (n = 412) Percent (95% CL) of pts with a transfusion (week 5 to EOTP) 31% (24, 38) (n = 179) 14% (11, 18) (n = 395) 20% (17, 23) (n = 602) Mean (95% CL) change in FACT-F from baseline at week 16 (available data approach) 4.7 (2.3, 7.1) (n = 128) 2.9 (1.2, 4.6) (n = 291) 3.5 (2.2, 4.9) (n = 424) Average (95% CL) Q3W dose administered 337 mcg (328, 345) 324 mcg (319, 330) 328 mcg (324, 333) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Genentech Amgen

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients

Darbepoetin alfa is an erythropoietis-stimulating glycoprotein with a ∼3-fold longer t1/2 and greater biological activity compared with recombinant human erythropoietin (rHuEPO). The objective of this study was to evaluate the efficacy andtolerability of long-term (24-week) darbepoetin alfa treatment in maintaining hemoglobin (Hb) concentrations in the target range of 10 to 13 g/dL in patients undergoing dialysis; the patients were switched from rHuEPO to a less-frequent dosing regimen of darbepoetin alfa without an increase in dose. In this Phase IIlb, open-label, multicenter study, patients withend-stage renal disease (ESRD) undergoing dialysis who were receiving rHuEPO BIW or TIW at baseline were switched to darbepoetin alfa QW; patients receiving rHuEPO QW were switched to darbepoetin alfa Q2W Administration of darbepoetin alfa was by the same route as previous rHuEPO administration (IV or SC). Patients received darbepoetin alfa for 24 weeks, including a 20-week drug titration period followed by a 4-week, stable-dose evaluation period. The mode, dose, and frequency of administration of darbepoetin alfa were compared with those of baseline rHuEPO. Tolerability assessment was based on spontaneous reporting and laboratory tests (hematology, vital sign measurement, iron status, and biochemistry). The study comprised 173 patients who were divided into 2 groups by route of administration (IV group, n = 146; SC group, n = 27). Mean (SE) adjusted increases in Hb concentration from baseline to the evaluation period for patients receiving darbepoetin alfa QW were 0.94 (0.32) g/dL and 0.38 (0.30) g/dL for the IV or SC routes, respectively ( P = 0.004 and NS, respectively). For patients receiving darbepoetin alfa Q2W the mean (SE) adjusted increases in Hb concentration were 0.08 (0.53) g/dL and 0.48 (0.35) g/dL for the IV and SC routes, respectively (both, P = NS). No significant differences in IV/SC dose ratio were observed between the 2 routes of administration. In addition, no increases in darbepoetin alfa dose were observed. The most commonly reported adverse events were hypertension (8 patients [5%]) and vascular access thrombosis (4 [2%]). The incidence of treatment-related adverse events was 6 (3%). Darbepoetin alfa effectively maintained Hb concentrations within the target range without an increase in dose, even at a reduced dosing frequency. Overall, darbepoetin alfa was well tolerated.

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients

Background: Darbepoetin alfa is an erythropoietis-stimulating glycoprotein with a ∼3-fold longer t1/2 and greater biological activity compared with recombinant human erythropoietin (rHuEPO). Objective: The objective of this study was to evaluate the efficacy andtolerability of long-term (24-week) darbepoetin alfa treatment in maintaining hemoglobin (Hb) concentrations in the target range of 10 to 13 g/dL in patients undergoing dialysis; the patients were switched from rHuEPO to a less-frequent dosing regimen of darbepoetin alfa without an increase in dose. Methods: In this Phase IIlb, open-label, multicenter study, patients withend-stage renal disease (ESRD) undergoing dialysis who were receiving rHuEPO BIW or TIW at baseline were switched to darbepoetin alfa QW; patients receiving rHuEPO QW were switched to darbepoetin alfa Q2W Administration of darbepoetin alfa was by the same route as previous rHuEPO administration (IV or SC). Patients received darbepoetin alfa for 24 weeks, including a 20-week drug titration period followed by a 4-week, stable-dose evaluation period. The mode, dose, and frequency of administration of darbepoetin alfa were compared with those of baseline rHuEPO. Tolerability assessment was based on spontaneous reporting and laboratory tests (hematology, vital sign measurement, iron status, and biochemistry). Results: The study comprised 173 patients who were divided into 2 groups by route of administration (IV group, n = 146; SC group, n = 27). Mean (SE) adjusted increases in Hb concentration from baseline to the evaluation period for patients receiving darbepoetin alfa QW were 0.94 (0.32) g/dL and 0.38 (0.30) g/dL for the IV or SC routes, respectively ( P = 0.004 and NS, respectively). For patients receiving darbepoetin alfa Q2W the mean (SE) adjusted increases in Hb concentration were 0.08 (0.53) g/dL and 0.48 (0.35) g/dL for the IV and SC routes, respectively (both, P = NS). No significant differences in IV/SC dose ratio were observed between the 2 routes of administration. In addition, no increases in darbepoetin alfa dose were observed. The most commonly reported adverse events were hypertension (8 patients [5%]) and vascular access thrombosis (4 [2%]). The incidence of treatment-related adverse events was 6 (3%). Conclusions: Darbepoetin alfa effectively maintained Hb concentrations within the target range without an increase in dose, even at a reduced dosing frequency. Overall, darbepoetin alfa was well tolerated.

Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein that functions by the same mechanism as recombinant human erythropoietin (rHuEPO), but has a three-fold longer serum half-life. Reduction in the frequency of darbepoetin alfa administration would be beneficial to patients with renal disease and their healthcare providers. This study evaluated the effect of extending the darbepoetin alfa dosing interval to once monthly in patients with chronic kidney disease (CKD) not receiving dialysis. This study was a multicenter, open-label study of 97 patients with CKD not on dialysis. Patients receiving stable subcutaneous doses of darbepoetin alfa once every two weeks were converted to darbepoetin alfa once monthly for 29 weeks. The proportion of patients who successfully maintained hemoglobin concentrations between 10.0 and 12.0 g/dl and the mean darbepoetin alfa dose were evaluated. Safety measurements (e.g. adverse events, laboratory parameters, blood pressure) and seroreactivity were assessed. Hemoglobin concentration was maintained within the target range in 79% (95% confidence interval (CI) = 71% to 87%) of all patients receiving darbepoetin alfa and in 85% (95% Cl = 78% - 93%) of patients who completed the study period. The mean +/- standard deviation monthly darbepoetin alfa dose was similar between baseline (88.7 +/- 49.9 microg) and the evaluation period (86.6 +/- 78.8 microg). The safety profile for monthly darbepoetin alfa administration was comparable with that previously observed with more-frequent administration. Patients with CKD who are clinically stable on darbepoetin alfa administered once every two weeks can be safely and effectively converted to darbepoetin alfa administered once monthly.

Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: A randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa

The introduction of longer-acting erythropoietic agents into the practice of oncology has demanded an understanding of the interaction of chemotherapy with the pharmacokinetics and haematological effects of these erythropoietins. We report results of a randomised trial comparing the haematological effects of darbepoetin alfa, 6.75 μg/kg, administered once every 3 weeks to anaemic cancer chemotherapy patients on either an asynchronous (day 15) or synchronous (day 1) schedule relative to their every-3-week chemotherapy. A total of 81 patients were randomised and received the study drug (43 asynchronous; 38 synchronous). No difference was observed between groups in the primary endpoint of mean haemoglobin change after 6 weeks of therapy ( P = 0.45) and change scores were similar to those observed with standard weekly darbepoetin alfa therapy. In a subset of patients evaluated with intensive pharmacokinetic sampling, an increase in endogenous erythropoietin concentration (up to 4-fold) lasting approximately 1 week following chemotherapy administration was observed in both groups. Synchronous administration of darbepoetin alfa was associated with a 1.3-fold increase in the area under the darbepoetin alfa concentration–time curve compared with asynchronous administration. Our data suggest that darbepoetin alfa is effective administered every 3 weeks regardless of timing of administration with respect to chemotherapy and that receptor-mediated uptake by the erythron may be an important clearance mechanism for erythropoietic proteins.

Cancer-Related Anemia

Anemia has a high prevalence in patients with cancer. Its frequency and severity depend on tumor type, tumor stage, duration of disease, and treatment status. The etiology of cancer-related anemia is multifactorial and includes myelotoxicity of treatment, bone marrow infiltration, impaired erythropoietin production, blood loss, and the anemia of chronic disease. Anemia affects health-related quality of life (QOL) and may impact on tolerance or even outcome of anticancer therapy. Despite its high prevalence and impact on QOL, anemia is often under-recognized and under-treated. Treatment should correct etiologic factors, whenever possible. Symptomatic treatments are red blood cell transfusions and administration of erythropoietic growth factors. Transfusions result in rapid improvement of anemia-related symptoms but are usually only given to patients with moderate to severe anemia. Administration of epoetins (epoetin alfa, epoetin beta) or darbepoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and improves QOL in patients with cancer-related anemia. Trials determining the exact association of anemia with both response to chemo(radio)therapy and survival are ongoing. Physicians should be aware of the clinical relevance of and treatment options for anemia in cancer patients.

Darbepoetin alfa Radiosensitizes Tumors Independent of Anemia or the Correction of Anemia.

Darbepoetin alfa (DA) is a FDA approved long acting erythropoietic protein. We hypothesized that correction of anemia in tumor-bearing mice by DA would secondarily increase the tumor pO2 and potentiate radiation-induced cell killing of tumor cells. To test this hypothesis, we used total body irradiation (TBI) to induce anemia in C3H mice. Murine squamous cell carcinoma tumor (SCC VII) and fibrosarcoma (RIF-1) models were used to study tumor responses to radiation in vivo. DA (30μg/kg) was administered i.p. either every two weeks or weekly. EPO-R RNA levels were measured in tumors from normal, anemic and DA treated mice in both tumor models. Tumors were locally irradiated with daily fractions of 250 cGy for 5 days. Following 500 cGy TBI, hemoglobin levels decreased and reached a nadir of 7.0 ± 0.9 gm/dL 14 days post TBI. Administration of DA reduced the depth and duration of anemia and improved the general health condition of anemic animals as evidenced by accelerated recovery of body weight following the TBI and maintenance of normal levels of activity compared to similarly irradiated animals not treated with DA. Mice treated with DA on the same day as the TBI had elevated hemoglobin levels with a nadir of 11.1 gm/dL on day 14 after TBI. Systemic administration of DA alone did not stimulate tumor growth in TBI-induced anemic mice. When combined with fractionated local tumor irradiation, administration of DA at any of the time points studied (18, 11, 4 and 0 days before initiation of local tumor irradiation) delayed tumor growth and increased the tumor growth delay time from 2.7 days for irradiation alone to 7.3 – 10.6 days for DA treated animals (p < 0.01). There was no statistically significant difference between tumor growth delay times for groups of mice treated with DA at various times before tumor irradiation. Although DA effectively corrected anemia in tumor-bearing mice and significantly decreased the number of hypoxic cells in the tumors as shown by EF5 staining, radiosensitization by DA was independent of the correction of anemia. EPOR RNA expression was barely detectible in tumors cultured in vitro. There were no differences in EPO-R RNA levels in tumors from anemic or DA treated mice (1–2 fold increase), although EPO-R transcription was upregulated in tumors grown in vivo compared to control tumors lines grown in vitro (40–80 fold increase). This may be due to hypoxic induction of EPO-R by tumors in vivo or expression of EPO-R by endothelial cells or infiltrating macrophages. Results from an experiment in non-anemic mice with RIF-1 tumors suggest that DA can sensitize tumor cells in non-anemic mice to radiation as well. These results support the idea that radiosensitization by DA is independent of hemoglobin and tumor pO2. It has long been assumed that anemia causes decreased tumor oxygenation and increased tumor radioresistance, and that correction of anemia would therefore increase tumor pO2, and result in enhanced radiosensitivity. However, the data presented here challenge this presumed relationship. These findings are promising and may have relevance to the treatment of patients with a variety of tumor types with radiation therapy.

Darbepoetin Alfa Effectively Treats Anemia in Patients with Chronic Kidney Disease with de novo Every-Other-Week Administration

Aim: This multicenter, open-label study determined safety and efficacy of once-every-other-week administration of darbepoetin alfa for anemia of chronic kidney disease in erythropoietin-naive patients not on dialysis. Methods: Participants with hemoglobin levels <11.0 g/dl at baseline were administered darbepoetin alfa at an initial dosage of 0.75 µg/kg once every other week. The dose was titrated to achieve and maintain a hemoglobin response, defined as a hemoglobin range of between 11.0 and 13.0 g/dl for up to 24 weeks. The primary end point was the dose of darbepoetin alfa at initial hemoglobin response. Results: Six hundred and eight patients were enrolled, and 463 completed the study; 95% (95% confidence interval: 0.93, 0.97) of the patients who completed treatment achieved a hemoglobin response. The mean darbepoetin alfa dose at the time of response was 63.5 ± (SD) 16.9 µg, and the mean time to hemoglobin response was 5.7 ± (SD) 4.5 weeks. Oral iron therapy was administered to 60% and intravenous iron to 16% of the participants. Darbepoetin alfa was well tolerated, and adverse events were consistent with those expected in patients with chronic kidney disease. Conclusion: Darbepoetin alfa administered once every other week is effective and safe for achieving and maintaining target hemoglobin levels in anemic patients with chronic kidney disease.

Supportive treatment for anemic cancer patients.

Anemia in cancer patients is frequent but often underestimated. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with cancer. Presently, trials investigate whether treatment of anemic cancer patients with erythropoietin impacts on outcome of chemo- and/or radiotherapy and on overall survival. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients. Supportive treatment of anemic cancer patients presenting anemia-related symptoms should be performed to reduce symptoms in cancer patients and optimize outcome to anticancer therapy.

Darbepoetin alfa: A new erythropoietic drug for the treatment of renal anaemia*

SUMMARY Darbepoetin alfa (Aranesp®, Amgen Ltd) is a long-acting, hyperglycosylated recombinant human erythropoietin (r-HuEPO; epoetin) analogue, developed for the treatment of anaemia in patients with chronic kidney disease (CKD, i.e. end-stage renal failure or progressive renal impairment). Based on previously published European guidelines, this review article presents key recommendations for the use of darbepoetin alfa in Australasian clinical practice. Darbepoetin alfa is expected to be a valuable alternative therapeutic agent for the management of renal anaemia. Clinical data demonstrate that: Once-weekly administration of darbepoetin alfa – whether by subcutaneous (s.c.) or intravenous (i.v.) injection – is as effective as epoetin therapy, administered two or three times per week; patients receiving once-weekly doses of epoetin can be switched to darbepoetin alfa, once every 2 weeks; target haemoglobin (Hb) concentrations can be successfully maintained in patients switched from epoetin therapy to less frequently administered doses of darbepoetin alfa (administration once every 2 weeks is sufficient for some patients); and darbepoetin alfa has a similar safety profile to epoetin. In addition to addressing a number of practical considerations relating to the use of darbepoetin alfa in clinical practice, this article also highlights principal findings from several key clinical studies.

Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients

Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency. A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment. The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected. Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.

An overview of the pharmacokinetic disposition of darbepoetin alfa.

Darbepoetin alfa is a new erythropoiesis-stimulating protein that has five carbohydrate chains compared with three in recombinant human erythropoietin (r-HuEPO, epoetin alfa). Owing to its increased carbohydrate content, the terminal half-life of darbepoetin alfa is 2-3-fold greater than that of r-HuEPO in patients with chronic kidney disease or cancer. This pharmacokinetic property may allow for less frequent administration of darbepoetin alfa compared with r-HuEPO. Although several regimens are still being tested, a predictable increase was observed in serum concentrations of darbepoetin alfa and no clinically relevant accumulation was seen with once-weekly administration for up to 48 weeks. Preliminary data in patients with cancer suggest that concurrent chemotherapy may influence the pharmacokinetics of darbepoetin alfa. Therefore, the timing of dosing relative to chemotherapy may be important. Darbepoetin alfa, through its potential for less frequent dosing, offers a more convenient treatment option than r-HuEPO for patients with anemia secondary to cancer or kidney disease.

Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients

Background: Darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) is a new erythropoiesis-stimulating protein with a threefold longer terminal half-life than recombinant human erythropoietin (epoetin) in patients with chronic kidney disease (CKD). The purpose of this randomized, double-blind, noninferiority study is to determine whether darbepoetin alfa is as effective as epoetin for the treatment of anemia in hemodialysis patients when administered at a reduced dosing frequency. Methods: Patients receiving epoetin therapy were randomized to continue epoetin administered intravenously (IV) three times weekly (n = 338) or change to darbepoetin alfa administered IV once weekly (n = 169). The dose of darbepoetin alfa or epoetin was individually titrated to maintain hemoglobin concentrations within −1.0 to +1.5 g/dL (−10 to +15 g/L) of patients' baseline values and within a range of 9.0 to 13.0 g/dL (90 to 130 g/L) for up to 28 weeks (20-week dose-titration period followed by an 8-week evaluation period). The primary end point was change in hemoglobin level between baseline and the evaluation period (weeks 21 to 28). Results: Mean changes in hemoglobin levels from baseline to the evaluation period were 0.24 ± 0.10 (SE) g/dL (2.4 ± 1.0 g/L) in the darbepoetin alfa group and 0.11 ± 0.07 g/dL (1.1 ± 0.7 g/L) in the epoetin group, a difference of 0.13 g/dL (95% confidence interval [CI], −0.08 ± 0.33 [1.3 g/L; 95% CI, −0.8 to 3.3]). This difference was not statistically significant or clinically relevant despite the reduced frequency of darbepoetin alfa administration. The safety profile of darbepoetin alfa was similar to that of epoetin, and no antibody formation to either treatment was detected. Conclusion: These results show that darbepoetin alfa maintains hemoglobin concentrations as effectively and safely as epoetin in patients with CKD, but with a reduced dosing frequency. © 2002 by the National Kidney Foundation, Inc.

Darbepoetin alfa: A new erythropoietic drug for the treatment of renal anaemia*

SUMMARY: Darbepoetin alfa (Aranesp®, Amgen Ltd) is a long‐acting, hyperglycosylated recombinant human erythropoietin (r‐HuEPO; epoetin) analogue, developed for the treatment of anaemia in patients with chronic kidney disease (CKD, i.e. end‐stage renal failure or progressive renal impairment). Based on previously published European guidelines, this review article presents key recommendations for the use of darbepoetin alfa in Australasian clinical practice.Darbepoetin alfa is expected to be a valuable alternative therapeutic agent for the management of renal anaemia. Clinical data demonstrate that: Once‐weekly administration of darbepoetin alfa ‐ whether by subcutaneous (s.c.) or intravenous (i.v.) injection ‐ is as effective as epoetin therapy, administered two or three times per week; patients receiving once‐weekly doses of epoetin can be switched to darbepoetin alfa, once every 2 weeks; target haemoglobin (Hb) concentrations can be successfully maintained in patients switched from epoetin therapy to less frequently administered doses of darbepoetin alfa (administration once every 2 weeks is sufficient for some patients); and darbepoetin alfa has a similar safety profile to epoetin. In addition to addressing a number of practical considerations relating to the use of darbepoetin alfa in clinical practice, this article also highlights principal findings from several key clinical studies.

Darbepoetin alfa.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.