Greg Rossi

Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin </=110 g/l) were randomised in a 1:4 ratio to receive 1 of 6 doses of darbepoetin alfa (4.5, 6.75, 9.0, 12.0, 13.5 and 15.0 microg/kg) or placebo Q3W for 12 weeks. In part B, patients received open-label darbepoetin alfa. Patients (n=249) were evaluated for safety, haemoglobin endpoints and red blood cell (RBC) transfusions. Darbepoetin alfa given at doses ranging from 4.5 to 15.0 microg/kg Q3W was well tolerated and comparable to placebo in terms of safety. No neutralising antibodies were detected. All doses (from 4.5 to 15 microg/kg) reduced transfusions compared with placebo, and resulted in >50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.

A Multicenter Retrospective Cohort Study of Practice Patterns and Clinical Outcomes of the Use of Darbepoetin Alfa and Epoetin Alfa for Chemotherapy-Induced Anemia

BACKGROUND Darbepoetin alfa is the second erythropoietic protein to be approved for the treatment of chemotherapy-induced anemia (CIA). In the clinical setting, darbepoetin alfa can be administered less frequently than epoetin alfa with similar efficacy. Practice patterns and outcomes associated with the use of darbepoetin alfa and epoetin alfa in the clinical setting have not been reported. OBJECTIVE This study compared practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for CIA at oncology practices in the United States. METHODS This was a multicenter retrospective cohort study. Data were abstracted from the medical charts of consecutive patients who began darbepoetin alfa treatment between August 1 and October 4, 2002, or epoetin alfa treatment between April 1 and July 31, 2002, and were receiving concurrent chemotherapy. These data were used to determine the initial dose and dosing schedule, dose changes, and changes in hemoglobin concentrations after 4, 8, and 12 weeks of treatment, adjusted for red blood cell (RBC) transfusions, and the incidence of RBC transfusions over time. To minimize potential bias, the study protocol defined specific end points and prespecified analytic techniques for assessing clinical outcomes with the 2 agents. RESULTS The records of 1391 patients from 16 community and hospital outpatient oncology clinics were abstracted. Of these, 1293 patients (93.0%) received only 1 erythropoietic agent (darbepoetin alfa, 735 [56.8%]; epoetin alfa, 558 [43.2%]); the remainder received both agents. In the patients who received darbepoetin alfa, most (553 [75.2%]) received an initial dosage of 200 microg q2wk. A similar proportion (414 [74.2%]) received epoetin alfa at an initial dosage of 40,000 U qwk. As these were the regimens for the majority of patients whose records were abstracted, the results reported here are for these patients. The dose was increased in 63 darbepoetin alfa recipients (11.4%) and 58 epoetin alfa recipients (14.0%) at a median of 7 weeks. After 12 weeks, the 2 groups had an identical mean imputed change from baseline in hemoglobin concentration (1.0 g/dL), and the incidence of RBC transfusions during treatment was also similar between groups (darbepoetin alfa, 44553 [8.0%]; epoetin alfa, 39414 [9.4%]). CONCLUSIONS Darbepoetin alfa 200 microg q2wk was used as a standard regimen for CIA at the 16 US oncology practices participating in this study. It appeared to be as effective as epoetin alfa 40,000 U qwk, with a reduced frequency of dosing.

Assessing symptom burden using the M. D. Anderson Symptom Inventory in patients with chemotherapy-induced anemia: Results of a multicenter, open-label study (SURPASS) of patients treated with darbepoetin-α at a dose of 200 μg every 2 weeks

Patients with cancer who are receiving chemotherapy often experience chemotherapy‐induced anemia (CIA), which is associated with symptoms that reduce quality of life. The M. D. Anderson Symptom Inventory (MDASI) is a brief, self‐rating assessment scale that measures the severity of core symptoms and symptom interference with function. The current study used the MDASI to prospectively assess the correlation between hemoglobin and self‐perceived cancer‐related symptoms in a large patient population with CIA who were receiving darbepoetin‐α at a dose of 200 μg every 2 weeks.

Pharmacokinetics of Darbepoetin Alfa after Intravenous or Subcutaneous Administration in Patients with Non-myeloid Malignancies Undergoing Chemotherapy

Background and objectiveThe pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was to evaluate the pharmacokinetics of IV or subcutaneous (SC) darbepoetin alfa in patients with non-myeloid malignancies undergoing multicycle chemotherapy.MethodsFifty-six patients (haemoglobin <13.0 g/dL) received weekly darbepoetin alfa 2.25 µg/kg administered either IV (n = 27) or SC (n = 29) during up to three cycles of chemotherapy. Noncompartmental pharmacokinetic analysis was performed, including analysis of intensive pharmacokinetic profiles collected over 168 hours during week 1 of both the first and third cycles of chemotherapy.ResultsDarbepoetin alfa serum concentrations exhibited a biphasic profile (a rapid distributive phase followed by a slower terminal elimination phase) after IV administration, whereas darbepoetin alfa was slowly absorbed after SC administration. Darbepoetin alfa exhibited limited extravascular distribution after IV administration, with both initial and steady-state mean volumes of distribution (36.1 mL/kg and 55.2 mL/kg, respectively, after a single IV dose) approximating the plasma volume. After a single IV dose, darbepoetin alfa exhibited a mean clearance of 1.05 mL/h/kg, with a mean terminal half-life of 38.8 hours. Similar pharmacokinetic results were observed after single and multiple doses of darbepoetin alfa, for both SC and IV administration.ConclusionDarbepoetin alfa is cleared slowly after IV administration to patients with cancer receiving chemotherapy, resulting in a terminal half-life of 38.8 hours. No evidence of accumulation and no changes in pharmacokinetic profiles after repeated administration were observed in cancer patients undergoing cyclic chemotherapy, for both IV and SC dosing.

A randomized, controlled trial comparing darbepoetin alfa correction/maintenance dosing with weekly dosing for treating chemotherapy-induced anemia.

ABSTRACT Objective: To evaluate if a darbepoetin alfa correction/maintenance dosing regimen is non-inferior to a weekly regimen with respect to red blood cell transfusion requirements in patients with chemotherapy-induced anemia (CIA). Research design and methods: In this randomized, active-controlled, double-blind phase 3 trial, CIA patients were randomized 1 : 1 to receive darbepoetin alfa in either a correction/maintenance schedule (4.5 μg/kg weekly for 4 weeks followed by 4.5 μg/kg every 3 weeks (Q3W)) or a weekly schedule (2.25 μg/kg weekly). The primary endpoint was the transfusion incidence during weeks 1–16. Non-inferiority was to be concluded if the upper limit of the 95% confidence interval (CI) of the difference in transfusion incidence between treatment groups was below 12.5%. Hematologic responses and safety profiles were also compared. Results: Transfusion incidence (95% CI) during weeks 1–16 was 37% (32–42) and 38% (32–43) in the weekly and correction/maintenance groups, respectively. The difference (95% CI) in transfusions was 0.4% (–7.0 to 7.8), demonstrating non-inferiority between treatment groups. Similar percentages in both groups achieved and maintained hemoglobin in a target range of 11–13 g/dL and had clinically meaningful FACT‑F score improvements. The median (range) time to hemoglobin response was 10 (1–17) weeks and 12 (2–17) weeks in the weekly and correction/maintenance groups, respectively. Both groups had similar safety profiles. Conclusions: A correction/maintenance schedule with its initial two-fold higher weekly dosing and subsequent Q3W dosing yielded outcomes similar to those observed with a weekly schedule. Although correction/maintenance dosing provided no incremental clinical benefit, Q3W dosing could provide benefits of convenience and facilitate patient compliance.

Pharmacokinetic evaluation of darbepoetin alfa for the treatment of pediatric patients with chemotherapy‐induced anemia

Cancer patients undergoing chemotherapy often develop anemia, which can increase the risk for transfusions and fatigue. The recombinant erythropoiesis‐stimulating agent darbepoetin alfa can effectively treat chemotherapy‐induced anemia (CIA) in adults, but limited data are available regarding its use in pediatric cancer patients. The goals of this phase 1, open‐label, uncontrolled study were to assess the pharmacokinetic profile and safety of darbepoetin alfa in pediatric patients with CIA.

The impact of timing of chemotherapy relative to darbepoetin alfa (DA) on DA pharmacokinetics (PK) and hematologic effects

DA is usually administered synchronously with chemotherapy (ctx). This study evaluated whether timing of DA dosing, relative to ctx, impacted its PK and efficacy. The study was conducted in anemic cancer patients receiving ctx once every 3 weeks (Q3W), randomized to receive DA 6.75 μg/kg Q3W either 1 week before ctx (asynchronous) or on the same day as ctx (synchronous) for up to 16 weeks. The effects of cyclic ctx on PK of DA and endogenous EPO levels were evaluated in a sub‐set of patients after 1st dose. 81 patients were randomized to receive study drug. Synchronous dosing resulted in higher maximal DA concentrations (mean ± SD) (26.5 ± 9.67 ng/mL, n=13) than asynchronous dosing (15.5 ± 5.25 ng/mL, n=12), with a 1.6‐fold increase in exposure (AUC) over week 1. However, DA concentrations increased between 7‐10 days post‐dose due to ctx administration at day 7 for the asynchronous group, resulting in a 1.4‐fold greater AUC for wks 2 and 3. DA terminal half‐life tended to be longer in the asynchronous group (87.7 ± 26.0 hr vs 60.9 ± 22.3 hr). In both groups, EPO was elevated for 1 week after ctx, with peak concentrations (4‐5‐fold increase) at 48 hr. Despite the PK differences, mean (95% CI) change in hgb at wk 7 was similar [0.95 (0.56, 1.33) g/dL vs 1.03 (0.58, 1.47) g/dL]. These results show that DA dosed once per cycle is effective in treating chemotherapy‐induced anemia. The findings also indicate that the bone marrow may play a role in the clearance of these agents.