Administration Of Darbepoetin Alfa Research Articles

Effect of darbepoetin alfa on endothelial progenitor cells and vascular reactivity in chronic kidney disease

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.

Treatment of Renal Anemia in Saudi Dialysis Patients: Between Darbepoetin Alfa and Recombinant Human Eryhthrpoietin (rHuEPO)

Background: Darbepoetin alfa is an erythopoietic agent with a 3-fold longer elimination half-life than recombinant human erythropoietin (rHuEPO), which allows less frequent dosing, and hence it maintains an effective hemoglobin control at extended dose intervals compared with rHuEPO. This study assessed the efficacy and safety of unit doses of darbepoetin alfa for the treatment of renal anemia in hemodialysis (HD) and peritoneal dialysis (PD) patients. Methods: In this prospective study, 143 dialysis patients (68 HD and 75 PD patients) maintained on stable rHuEpo treatment were switched to darbepoetin alfa at extended dose intervals by the same route of administration as previous rHuEpo therapy [intravenous (i.v.), n=78 or subcutaneous (s.c.), n= 65]. Patients receiving rHuEpo two or three times a week were switched to darbepoetin alfa once a week and those receiving rHuEpo once a week were switched to darbepoetin alfa once every two weeks. The unit doses of darbepoetin alfa (10-150 ug) were titrated to maintain hemoglobin concentrations of 10-12 g/dl for 24 weeks. Results: Hemoglobin (Hgb) concentrations were maintained effectively in our patients regardless of the dose interval of darbepoetin alfa. The overall mean change in Hgb concentration from baseline to evaluation period was an increase of 0.18 g/dl (95% CI ± 0.16). Regardless of route of administration, darbepoetin alfa effectively maintained mean Hgb concentration above 11 g/dl throughout the entire study period. Darbepoetin alfa administered by both the i.v. and s.c. routes resulted in stable mean Hgb concentrations during the evaluation period. Subjects with baseline Hgb concentrations < 11 g/dl experienced significant mean increase in Hgb concentration from baseline to evaluation, which was more pronounced following i.v. than s.c. administration (0.79 vs o.55 g/dl respectively). Relative to baseline, i.v. and s.c. darbepoetin alfa dosage requirements decreased in subjects with baseline Hgb ≥11g/dl (21.64 to 15.86 ug/week and 21.95 to 18.52 ug/week respectively p =0.0214), while there was a little increase in darbepoetin alfa dosage in subjects with baseline Hgb < 11 g/dl (25.22 to 26.76 ug/week and 22.74 to 24.81 ug/week in the i.v. and s.c. groups respectively p=0.0581). The percentage change in dose requirements from baseline to evaluation period in all patients, regardless of route of administration was not significant (2.28%, 95% CI -3.64, 7.89). Hemoglobin concentrations were also effectively maintained in patients who received darbepoetin alfa once weekly and once every other week. Darbepoetin alfa was well tolerated in all HD and PD patients, and the safety profile was consistent with previous trials with darbepoetin alfa in dialysis patients. Conclusion: The treatment of renal anemia in dialysis patients (both HD and PD) with unit doses of darbepoetin alfa is both effective and well tolerated. Moreover, administration of darbepoetin alfa by both i.v. and s.c. route is associated with stable Hgb concentration. Darbepoetin alfa administered i.v. or s.c once weekly or once every other week is an effective and safe treatment regimen for hemodialysis and peritoneal dialysis patients with renal anemia.

Addition of Darbepoetin Alfa to Dose-Dense Chemotherapy: Results From a Randomized Phase II Trial in Small-Cell Lung Cancer Patients Receiving Carboplatin Plus Etoposide

Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group’s QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.

Randomized Phase 2 Dose-finding Study of Weekly Administration of Darbepoetin Alfa in Anemic Patients with Lung or Ovarian Cancer Receiving Multicycle Platinum-containing Chemotherapy

This is the first clinical trial for Japanese to evaluate the dose-response and determine the clinically effective dose of darbepoetin alpha by weekly subcutaneously administration in anemic patients with lung cancer or ovarian cancer receiving chemotherapy. Eligible patients were required to have anemia (hemoglobin level of <or=11.0 g/dl). Patients were randomized in a 1:1:1 ratio to receive darbepoetin alpha (1.0, 2.25 or 4.5 microg/kg) subcutaneously once a week for up to 12 weeks. The study drug was withheld from patients who had a hemoglobin level >15.0 g/dl (for men) or 14.0 g/dl (for women), and reinstated at 50% of the previous weekly dose when the hemoglobin level decreased to <or=13.0 g/dl. Quality-of-life assessments were conducted using the Japanese version of the Functional Assessment of Cancer Therapy-anemia (FACT-an) questionnaire. Hemoglobin response rate was 31.6%, 55.6% and 70.3% in 1.0, 2.25 and 4.5 microg/kg groups, respectively. The dosages of 2.25 and 4.5 microg/kg thus met the clinically effective dose criterion of at least 50% of patients achieving a hemoglobin response. The FACT-fatigue subscale had a high internal consistency with Cronbach's alpha score. Although no improvement in FACT-fatigue subscale score from baseline to the end of the treatment phase was confirmed for any dose group, there was a correlation between FACT-fatigue subscale score and hemoglobin concentration. Darbepoetin alpha appears to be well tolerated in this setting and no dose-dependent adverse events were observed. Darbepoetin alpha alleviated anemia caused by platinum-based chemotherapy, and the dosage of 2.25 microg/kg was the lowest dose that met the clinically effective dose criteria when administered once weekly.

The efficacy of monthly administration of darbepoetin alfa in Saudi hemodialysis patients

AbstractBACKGROUNDErythropoiesis‐stimulating agents have improved the outcome and quality of life in patients with chronic kidney disease.OBJECTIVEWe investigated the efficacy and safety of conversion of hemodialysis patients from epoetin beta to darbepoetin alfa administered once a month.PATIENTS AND METHODSThe study included 26 patients. Their mean age was 47.0 6 17.13 years with a mean hemodialysis duration of 55.8 ± 14.0 months. The study was carried out in 2 consecutive phases of 12 weeks each. The mean initial dose of darbepoetin was 57 ± 10.0 mg biweekly. After maintaining target hemoglobin (Hgb) levels—(11–12 g/L)—with the biweekly injections, we shifted our patients to a once‐monthly dose schedule.RESULTSThe mean weekly darbepoetin dose increased from 28.75 ± 4.2 mg during the biweekly phase to 38.5 ± 3.9 mg after switching to the monthly protocol (the mean conversion ratio changed from 309:1 to 256:1). The mean Hgb level was 10.81 ± .86 g/L at the start of the study and 10.86 ± .76 g/L at the end of 6 months.CONCLUSIONOur experience with darbepoetin alfa reveals that it is effective and safe for the treatment of anemia in hemodialysis patients even at monthly dose intervals.

Timing of the administration of intravenous darbepoetin alfa during the dialysis session: Does it impact efficacy?

AbstractBACKGROUNDDarbepoetin alfa (DA) is an erythropoietin‐stimulating agent (ESA) preferably administered through intravenous (IV) route in hemodialysis (HD) patients. Although some in vitro studies suggest the possibility of partial adsorption of ESAs in dialysis membranes (Mb) and lines, these data are not clinically confirmed.METHODSThis 12‐month, prospective, single‐center cross‐over study assessed the impact of the time of IV DA injection during HD on hemoglobin (Hgb) level and ESA dosing. A total of 90 HD patients received IV DA once every other week (Q2W), delivered at 2 possible time points: the middle or end of the HD session. After 6 months, the injection time point was crossed over to the other timing modality for another 6 months.RESULTSDemographics for both groups of patients were similar. Mean Hgb level remained stable from baseline to month 6 (not significant) for both timing modality groups. The same was observed for DA dose. Hemodialysis session parameters, nutritional status, and Kt/V were similar and stable during the study. Mean transferrin saturation was 44% and serum ferritin was $100 mg/L in more than 92% of patients. Iron supplementation remained unchanged and there were no blood transfusions during the study.CONCLUSIONSQ2W DA maintained target Hgb concentrations. The lack of difference in Hgb levels and DA dosing between the 2 injection timings suggests a lack of clinically significant adsorption/interaction between DA and dialysis Mb/lines. Therefore, timing of IV DA administration can be flexible and adapted to the routine practice of each local dialysis unit.

Every-Other-Week Darbepoetin Alfa in the Correction and Maintenance of Haemoglobin Levels in Elderly Patients with Chronic Kidney Disease

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy. This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort. This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years). A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis. The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.

Design of the Reduction of Events with Darbepoetin alfa in Heart Failure (RED‐HF): a Phase III, anaemia correction, morbidity–mortality trial

Patients with heart failure (HF) and anaemia have greater functional impairment, worse symptoms, increased rates of hospital admission, and a higher risk of death, compared with non-anaemic HF patients. Whether correcting anaemia can improve outcomes is unknown. The Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF; Clinical Trials.gov NCT 003 58215) was designed to evaluate the effect of the long-acting erythropoietin-stimulating agent darbepoetin alfa on mortality and morbidity (and quality of life) in patients with HF and anaemia. Approximately 2600 patients with New York Heart Association class II-IV, an ejection fraction < or =40%, and a haemoglobin (Hb) consistently < or =12.0 g/dL but > or =9.0 g/dL will be enrolled. Patients are randomized 1:1 to double-blind subcutaneous administration of darbepoetin alfa or placebo. Investigators are also blinded to Hb measurements and darbepoetin alfa is dosed to achieve an Hb concentration of 13.0 g/dL (but not exceeding 14.5 g/dL) with sham adjustments of the dose of placebo. The primary endpoint is the time to death from any cause or first hospital admission for worsening HF, whichever occurs first. The study will complete when approximately 1150 subjects experience a primary endpoint.

Randomized trial to compare the dosage of darbepoetin alfa by administration route in haemodialysis patients

The doses of darbepoetin alfa required to maintain target haemoglobin levels after s.c. or i.v. administration when recombinant human erythropoietin (rHuEpo) treatment was replaced by darbepoetin alfa treatment in haemodialysis (HD) patients were compared. In this prospective, randomized, open-label study, 65 HD patients who were receiving stable SC doses of rHuEpo were switched to an equivalent dose of darbepoetin alfa at a reduced frequency by s.c. or i.v. administration. Patients were randomly assigned to the s.c. group (n = 32) or the i.v. group (n = 33). Darbepoetin alfa doses were titrated to maintain target haemoglobin levels of 8.0-11.0 g/dL for up to 24 weeks. A period of 20 weeks was used for dose titration and haemoglobin stabilization. This was followed by a 4 week evaluation period. The mean haemoglobin concentration during the evaluation period was similar in the s.c. and i.v. groups. The mean dose and mean weight-standardized dose of darbepoetin alfa during the evaluation period tended to be lower in the s.c. group than the i.v. group, although these differences were not statistically significant. The mean weekly darbepoetin alfa dose requirements during the evaluation period significantly decreased in both groups compared to the dose requirements at randomization. There is a possibility that s.c. administration of darbepoetin alfa is more efficacious than i.v. administration, but a definite benefit cannot be demonstrated with the current sample size. A bigger sample size is needed to confirm the result.

Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia

ABSTRACTObjective: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA.Research design and methods: Patients aged ≥ 18 years with anemia (hemoglobin <11 g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300 μg (n = 193) or placebo (n = 193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules.Main outcome measures: The primary endpoint was the proportion of patients who received ≥1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration ≥11 g/dL and subsequently maintaining hemoglobin levels above 11 g/dL, and the change in hemoglobin concentration over time.Results: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p < 0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were ≤8.0 g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups.Conclusions: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA.Trial registration: ClinicalTrials.gov identifier: NCT00110955.

Evaluation of clinical use of darbepoetin alfa in patients with chemotherapy-induced anemia

e20585 Background: Chemotherapy-induced anemia (CIA) is a frequent complication of patients (pts) with cancer and could be treated with erythropoiesis-stimulating agents such darbepoetin alfa (DA). The aim of this study was to investigate the patterns of use and effect of DA to treat CIA in clinical practice conditions. Methods: This was an observational, retrospective, multicenter study performed in 58 Spanish centres. Eligible pts were ≥18 yrs, diagnosed with non-myeloid malignancies and treated with chemotherapy (CT) and DA from October 2005 to October 2006. Data on demographic and clinical characteristics, CT and radiotherapy (RT), DA administration, red blood cell (RBC) transfusions, and haemoglobin (Hb) levels were collected from DA treatment initiation up to a maximum of 16 weeks or until treatment discontinuation. Results: A total of 685 pts were included in the study. Median age was 64.66 years (range 18.54–88.95), 50.7% were women, 74.11% had ECOG status 0–1 and 71.38% had stage III/IV cancer. Solid tumours represented 72.55% of the cases. The CT regimen included platinum derivates in 33.58% of the pts. At DA initiation, mean (SD) Hb was 10.00 g/dL (1.05) Administration of DA every three weeks occurred in 54.01% of the pts. Mean (SD) DA administration was 9.20 weeks (5.31). Hematopoietic response (defined as Hb ≥ 12 g/dL or Hb rise from baseline &gt;2 g/dL in the absence of RBC transfusions during the previous 28 days) occurred in 63.24% (95% CI 59.49–66.83) of pts. A total of 88 pts (12.85%) required RBC transfusions from week 5 to end of treatment. Mean Hb (SD) at the end of treatment with DA was 11.36 g/dL (1.73). Adverse event (AE) potentially related to DA were reported in 20 pts (2.92%) and considered severe in 6 cases (0.88%). Conclusions: The findings of this study indicate that the use of DA for the treatment of CIA in real-life, daily oncology and haematology practice, is well-tolerated and effective for increasing haemoglobin to reduce the need of RBC transfusions. [Table: see text]

Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are both characterized by the infiltration of myelin-reactive T cells that trigger oligodendrocyte death associated with axonal loss and neurodegeneration in the CNS. Proteolysis of the cerebral vascular extracellular matrix (ECM) resulting in blood-brain barrier (BBB) breakdown is thought to facilitate infiltration of autoreactive T cells in both of these demyelinating disorders. Increased matrix metalloprotease (MMP) activity coupled with reduced levels of tissue inhibitor of metalloproteases (TIMPs) contribute to a loss of BBB integrity. Erythropoietin induces expression of TIMP-1 in endothelial cells suggesting this property may account in part for its ability to maintain BBB integrity and efficacy in a preliminary clinical MS trial. Consistent with this hypothesis, we report here that administration of the erythropoietin analogue darbepoetin alfa at a low dose that did not elevate hematocrit reduced EAE severity in female C57BL/6 mice when administered following the onset of clinical signs. The protective effects of darbepoetin alfa were associated with an increase in the number of astrocytes expressing TIMP-1 in the brain and spinal cord. In keeping with a central role for TIMP-1 in this autoimmune model of acute demyelination, TIMP-1 null mice displayed a more severe EAE phenotype than wild-type littermates. Interestingly, we observed a lack of effect of darbepoetin alfa on EAE severity in TIMP-1 null mice. These findings indicate that TIMP-1 deficiency both enhances disease severity and attenuates the beneficial effects of low dose darbepoetin alfa in a mouse model of EAE.

Changing the frequency of administration of darbepoetin alfa (from weekly to fortnightly) maintains the haemoglobin levels in patients undergoing peritoneal dialysis

Less frequent dosing regimens during anemia treatment could benefit Peritoneal Dialysis (PD) patients. We investigated the effectiveness of darbepoetin alfa dosed every-other-week (Q2W) for maintaining hemoglobin (Hb) levels (11-13 g/dL). One hundred and nine PD patients from 14 centers participated in an 8-month observational, prospective study. Patients (Hb 11-13 g/dL) receiving weekly (QW) darbepoetin alfa switched to Q2W dosing at the investigator's discretion. Doses were adjusted according to published guidelines. Sixty-nine percent (75 out of 109) of patients switched to Q2W dosing. Thirty-three percent maintained the g/week, equivalent to twice the previous mean weekly dose (26.1-25.8 g/week, QW dose). Forty-seven percent received a dose reduction (35.8-20.2 equivalent to the previous QW dose). More patients in the maintenance dose group 11 g/dL than those receiving a reduced weekly dose (80% vs. had Hb levels 51.4%, respectively, p = 0.0236). During the Q2W phase, the mean Hb level ranged from 12.0-12.5 g/dL for the maintenance dose group and 11.5-12.0 g/dL for the reduced dose group. From the switch to the end of the study, the mean (SD) change in Hb was -0.7 g/dL (0.98 g/dL, p = 0.0557) and -0.6 g/dL (1.6 g/dL, p = 0.1296) for the maintenance and reduced dose groups, respectively. The Q2W darbepoetin alfa was well tolerated. Only a single treatment-related adverse event (polycythemia) occurred. The majority of PD patients receiving QW darbepoetin alfa can be effectively switched to Q2W and still maintain their Hb level.

A prospective observational study of the effectiveness, safety, and effect on fatigue of darbepoetin alfa for the treatment of chemotherapy-induced anaemia

ABSTRACTObjective: Anaemia is common in cancer patients treated with chemotherapy. Darbepoetin alfa (DA) is the only erythropoiesis-stimulating protein approved for administration at weekly and every-three-week intervals in cancer patients receiving chemotherapy. This article investigates the effectiveness, tolerability and effect on fatigue of DA.Methods: Prospective, observational study performed in 30 Spanish centres. Eligible patients were ≥ 18 years of age, anaemic (haemoglobin [Hb] ≤ 11 g/dL), with non-myeloid malignancies, receiving chemotherapy. DA (150 μg) was administered weekly for a maximum of 16 weeks (dosage doubled if Hb increased < 1 g/dL after 4 weeks).Main outcome measures: Haematopoietic response (Hb increase ≥ 2 g/dL or Hb ≥ 12 g/dL in the absence of transfusions in the previous 28 days), transfusion required between Weeks 5 and 16 and fatigue measured by the Fatigue subscale of the Functional Assessment of Cancer Therapy.Results: 293 adults were recruited (56.4% women), with lymphoproliferative malignancies (44.3%) or solid tumours (55.7%). Baseline Hb was 9–11 g/dL in 83.7% of patients. Sixty-four per cent (95% CI: 58.1–69.4%) had a haematopoietic response and 12% required transfusions. After adjusting for performance status, concomitant diseases and chemotherapy type, an increase in Hb level was significantly associated with an improvement in Fatigue subscale (+1.9 points per 1 g/dL). Only 2% of patients had treatment-related adverse events: thromboembolic pulmonary disease (0.3%); hypersensitivity reaction (0.3%); local pain following DA administration (0.3%); insomnia (0.3%); thrombocytosis (0.3%) and deep vein thrombosis (0.3%).Conclusions: Fixed-dose DA administered once weekly seems to be an effective, well-tolerated treatment for chemotherapy-induced anaemia in patients with non-myeloid malignancies, and there is an indication of a possible benefit on fatigue in the clinical practice.

Change in Darbepoetin Alfa Administration Schedule Affects Erythropoiesis-Stimulating Agent Resistance in Patients with Chronic Kidney Disease Receiving Hemodialysis

One hundred and four patients receiving hemodialysis and undergoing anaemia treatment with darbepoetin alfa intravenously once weekly were switched to a biweekly dosing schedule and followed for 24 weeks. The darbepoetin alfa dose was adjusted to maintain the target Hb concentration of 11–14 g/dL. A significant decline in the erythropoiesis-stimulating agent resistance index was observed over the 24-week follow-up, beginning with week 16, whereas the mean dose of darbepoetin alfa did not change significantly after switching to the biweekly dosing schedule. Other factors that might affect resistance to erythropoiesis remained unchanged.

Neuroprotective potential of erythropoietin and darbepoetin alfa in an experimental model of sciatic nerve injury

Object The objectives of this study were to examine whether the systemic administration of recombinant human erythropoietin (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery in a rat model of sciatic nerve injury, and to compare the effects of these agents in the model. Methods Thirty male Sprague–Dawley rats received a crush injury to the left sciatic nerve and subsequently underwent either placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Results Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment and improving compound muscle action potentials following nerve injury. Darbepoetin alfa, however, shortened the duration of peripheral nerve recovery and facilitated recovery from the neurological and electrophysiological impairment following crush injury significantly better than rHuEPO. Examination of the footprint length factor data revealed that darbepoetin alfa–treated animals recovered preinjury function by postoperative Day 10, 4 days earlier than animals treated with rHuEPO and 11 days earlier than animals treated with placebo. Conclusions These results suggest that recovery of neurological function in a model of peripheral nerve injury is more rapid with weekly administration of darbepoetin alfa than with daily rHuEPO treatment. Agents that facilitate nerve regeneration have the potential to limit the extent of motor endplate loss and muscle atrophy. The administration of EPO in its long-lasting recombinant forms affords significant neuroprotection in peripheral nerve injury models and may hold promise for future clinical applications.

Neuroprotective potential of erythropoietin and darbepoetin alfa in an experimental model of sciatic nerve injury

The objectives of this study were to examine whether the systemic administration of recombinant human erythropoietin (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery in a rat model of sciatic nerve injury, and to compare the effects of these agents in the model. Thirty male Sprague-Dawley rats received a crush injury to the left sciatic nerve and subsequently underwent either placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment and improving compound muscle action potentials following nerve injury. Darbepoetin alfa, however, shortened the duration of peripheral nerve recovery'and facilitated recovery from the neurological and electrophysiological impairment following crush injury significantly better than rHuEPO. Examination of the footprint length factor data revealed that darbepoetin alfa-treated animals recovered preinjury function by postoperative Day 10, 4 days earlier than animals treated with rHuEPO and 11 days earlier than animals treated with placebo. These results suggest that recovery of neurological function in a model of peripheral nerve injury is more rapid with weekly administration of darbepoetin alfa than with daily rHuEPO treatment. Agents that facilitate nerve regeneration have the potential to limit the extent of motor endplate loss and muscle atrophy. The administration of EPO in its long-lasting recombinant forms affords significant neuroprotection in peripheral nerve injury models and may hold promise for future clinical applications.

Baseline Characteristics of 65 Subjects in the Correction of Anemia with Darbepoetin alfa (DA) in the Community-Dwelling Frail Elderly (CAFÉ) Study.

Introduction: A growing body of literature has shown a strong and independent association between anemia and poor outcomes in older adults. Approximately one-third of all reported cases lack an obvious cause (i.e., unexplained anemia (UA)). The ongoing CAFÉ study aims to evaluate the impact of anemia correction on Quality of Life (QoL), as measured by the SF-36, in community-dwelling adults 70 years and older with UA. Described here are baseline characteristics from the first 65 subjects.Methods: A prospective, randomized, placebo-controlled, 24-week blinded study followed by an optional 22-week open-label extension. Participating subjects were anemic, non-dialysis, ambulatory, community-dwelling adults that met at least one criteria of the Frailty Index. Major enrollment criteria required a hemoglobin (Hb) ≥ 9.0 but <11.5 g/dL, estimated GFR > 30 ml/min/1.73m2, and adequate stores of iron, B12 and folate. Subjects were randomized 1:1 to either darbepoetin alfa (DA) starting at 60 mcg Q2W or placebo for 22 weeks. Hb was monitored every two weeks to ensure a rate of rise not to exceed 2 g/dL. QoL was measured by a Geriatric Panel at randomization (baseline) and weeks 10, 24, 36 and 48. QoL and physical function were also measured at baseline, week 12 and week 28.Results: The baseline characteristics (mean ± SD) are reported in Table 1. The mean Hb was 10.9 g/dL and mean C-reactive protein was 1.4 mg/L. Subjects had a mean serum creatinine of 1.2 mg/dL ± 0.4 g/dL and an estimated GFR of 54.8 ± 21.4 ml/min/1.73m2. Inadequate serum erythropoietin (EPO) for the degree of anemia was nearly universal (mean EPO = 19.8 ± 13.9 mU/ml, range = 4–27 mU/ml). The mean QoL scores were consistent with those observed in prior observational studies.Table 1Baseline characteristics of the study patients (n=65)DemographicsHematologyAge81.3 (6.5) (range = 70–95)Hemoglobin10.9 ± 0.6MCV93.6 ± 16.5SexReticulocyte count1.2 ± 0.5Men39 (63.9%)Women22 (36.1%)ChemistryRaceSerum iron71.8 ± 27.1White52 (82.5%)Iron Binding Capacity335.7 ± 85.7Black10 (15.9%)Percent Iron Saturation22.3 ± 10.4Middle Eastern1 (1.6%)Ferritin171.4 ± 249.9Creatinine1.2 ± 0.4Geriatric PaneleGFR54.8 ± 21.4BUN25 ± 8.5Frailty IndexEPO19.8 ± 13.90–110 (16.7%)Albumin3.9 ± 0.82–334 (56.7%)ESR32.9 ± 17.94–516 (26.7%)CRP1.4 ± 2.2Grip Strength19.2 ± 8.8MMSE28.5 ± 1.8FACIT-An49.6 ± 12.8SF-3657.7 ± 16.6CES-D11.2 ± 9.8IADL12.1 ± 3.0Conclusion: Baseline summary statistics for subjects in the CAFÉ study showed UA to be a mild normocytic hypoproliferative anemia exhibiting minimal elevation of inflammatory markers. The low serum EPO observed suggests that renal endocrine insufficiency may contribute to the pathogenesis of UA and further supports a trial evaluating the impact of DA administration on correction of anemia. The data further show that enrolling frail, community-dwelling, elderly adults having UA in an interventional trial is feasible.

Utilization of Darbepoetin alfa in Relation to Cancer Patients' Hemoglobin Levels.

Background: Prevailing guidelines through 2006 recommended initiating erythropoiesis stimulating agents (ESAs) for chemotherapy-induced anemia (CIA) at hemoglobin (Hb) levels <11 g/dL, maintaining near 12 g/dL, and withholding at >13 g/dL.Objective and Purpose: To determine darbepoetin alfa (DA) administration patterns in cancer patients and selected factors related to such use.Methods: A retrospective ESA administration-level analysis of Varian Medical Systems electronic medical records (EMRs), which includes 122,985 cancer patients across 13 states and 82 physical sites of care. The study period was 1/1/2005 – 11/30/2006. All DA administrations were recorded with the most recent Hb (day of or up to 7 days prior to administration). The proportion of DA administrations at Hb ≥ 12 and Hb ≥ 13 g/dL were the primary outcome measures. Utilization by Hb level was analyzed for all administrations, stratifying by year, gender, and anemia type. The types of anemia assessed were CIA, anemia of cancer (AOC), and myelodysplastic syndrome (MDS).Results: During the 23 month period, there were 33,923 DA administrations associated with Hb results in 5,252 patients. The proportion of all DA administrations given at Hb≥12 was 7.7%, for Hb≥13 g/dL it was 1.1%; proportions for CIA, AOC, and MDS were 8.1 /1.2% (N = 25,638 administrations), 7.5 /1.0% (N = 7,054), and 2.3 /0.2% (N = 1,231) for Hb ≥12 and ≥13 g/dL respectively. The difference across all three indications was statistically significant (P < 0.005) for both Hb thresholds. Overall, the proportion of all DA administrations at Hb ≥12 g/dL and ≥13 g/dL declined from 8.6% to 7.1% (p<.0001) and from 1.3% to 1.0% (p<.06) respectively in 2005 vs. 2006.Conclusions: In this population, DA administration at Hb ≥ 12 and Hb ≥ 13 occurred in approximately 7.7% and 1.1% of administrations, respectively. The results suggest that for the majority of administrations the prevailing guidelines at the time were adhered to by clinicians. Further research is required to understand dose titrations at Hb from 12 – 13 g/dL.

Anemia Management in Adult Chronic Hemodialysis Patients Using Darbepoetin Alfa Protocol

AbstractBACKGROUNDData on darbepoetin alfa for anemia management in patients with chronic kidney disease (CKD) is scarce when compared with epoetin alfa. Clinical experiences of using darbepoetin alfa, dosing guide, and average weekly requirements are discussed in this article.METHODSA retrospective data analysis of 150 adult chronic hemodialysis patients was conducted for the period January 2005–May 2006. Darbepoetin alfa administration used convenient pre‐filled syringes. Dose was titrated up or down in small increments to target hemoglobin (Hgb) levels of at least 11 and less than 13 g/dL. Hgb levels were measured twice monthly with the goal of maintaining 80% of patients at the target of 11 g/dL or greater. Intravenous iron was administered to maintain serum ferritin levels between 100 and 600 ng/mL and transferrin saturation between 20% and 45%. Other parameters monitored included average weekly darbepoetin alfa dose.RESULTSThe average percentage of patients maintained at an Hgb level of 11 g/dL or greater was: January–June 2005, 76.5% (95% CI, ± 2.56); July–December 2005, 82% (95% CI, ± 2.12); and 2006, 78.6% (95% CI, ± 2.96). The percentage of patients with an Hgb &gt; 12 g/dL was 21%–46%. The average weekly darbepoetin alfa doses decreased from 70 ± 3 µg (January–June 2005) to 62 ± 2 µg (June–December 2005) and further decreased to 55 µg (95% CI, mean ± 1.12) in 2006.CONCLUSIONSDarbepoetin alfa is effective for anemia management in CKD patients. The average weekly darbepoetin alfa requirement for anemia management to target an Hgb level of 11 g/dL or greater for most adult chronic hemodialysis patients is 55 µg or less.