Grossi et al intermediate 1 risk according to IPSS, Mannone and colleagues (2006) obtained an overall erythroid response of 71%, comparable with that observed in patients treated with the rHuEpo alpha plus G-CSF combination. Darbepoetin every-other- week The pharmacokinetic characteristics of the Darbepoetin suggest that Q2W or longer intervals between administrations are made possible. In an open-label study, Vadhan-Raj and colleagues (2003) evaluated the ability of darbepoetin alpha to reverse chemotherapy-induced anemia in cancer patients, induce changes in fatigue and functional capacity and their relation to hemoglobin increase in patients with hemoglobin ≤11 g/dL with nonmyeloid malignancy receiving multicycle chemotherapy. Darbepoetin alpha was administered at a starting dosage of 3 µ g/kg Q2W for up to eight doses (16 weeks). The interim analysis included a total of 1174 patients: mean increase in hemoglobin was 1.7 g/ dL (ITT analysis) and 2.1 g/dL for those patients receiving the full 16 weeks of therapy. The Kaplan-Meier estimate of the proportion of subjects with a hematopoietic response (increase in hemoglobin ≥2 g/dL and/or ≥12 g/dL) was 84%. To summarize the results of this study: a) darbepoetin determined an hemoglobin response (greater in patients with hemoglobin <10 g/dL) during treatment; b) the FACT-F subscale score increased by a mean of 6.8 points (26%) during the study; c) improvements in fatigue score paralleled the increases observed in hemoglobin. In conclusion the efficacy of the Q2W regimen of darbepoetin alpha is no different from that of weekly or three times per week rHuEpo. Glaspy and colleagues (2002) tested the administration of darbepoetin in a randomized multi-arm study in which different doses of darbepoetin (3 µ g/kg, 5 µ g/ kg, 7 µ g/kg, 9 µ g/kg) Q2W were given to patients on chemotherapy, and compared with the activity of a fixed weekly dose (40 000) of rHuEpo alpha. 60 000 U weekly could be used if hemoglobin increase was <1 g/dL. The study showed that darbepoetin Q2W is as effective as rHuEpo QW, and doses of darbepoetin higher than 5 µ g/kg do not increase the response. The feasibility of Q2W approach was confirmed by Patton and colleagues (2004) in a retrospective observational cohort study in which patients with chemotherapy-induced anemia received darbepoetin 100 µ g/ kg QW, darbepoetin 200 µ g/kg Q2W or rHuEpo (40 000 U QW), and by other authors (Schwartzberg et al 2004; Senecal et al 2005; Waltzman et al 2005). Herrington and colleagues (2005) derived data from 1444 patients treated with darbepoetin alpha and 1341 with 272 epoetin alpha. The most common initial dosages were 200 µ g Q2W for darbepoetin alpha (61%), and 40 000 U QW epoetin alpha (72%). The dosage was escalated for 22% of darbepoetin alpha recipients and 23% of epoetin alpha recipients at a median of six weeks after the initial dose. The mean change from baseline in hemoglobin concentration after 12 weeks of therapy was similar for both groups, as well as the percent of patients receiving red-blood-cell transfusions during treatment. Other schedules The possibility to further prolong the interval between administrations of darbepoetin in patients with cancer chemotherapy-induced anemia has also been explored. Kotasek and colleagues (2003), in a dose finding (from 4.5 µ g/kg to 15 µ g/kg by 2.5 µ g/kg steps) placebo-controlled study, observed that at all doses given darbepoetin Q3W reduced transfusion requirements compared with placebo, and hemoglobin increase was dose-dependent, with an increase ≥1 g/dL at doses of 6.75 mg/kg or greater. Fact-F fatigue score also improved with increasing hemoglobin concentration (p=0.0023), and safety profile was comparable in darbepoetin- and placebo-treated patients. Glaspy and coworkers (2005) studied whether timing in respect to chemotherapy influences eff icacy of darbepoetin Q3W. A dose of 6.75 µ g/kg Q3W was administered synchronously (starting on chemotherapy day 1, patients 38) or asynchronously (starting on chemotherapy day 15, patients 43) with concurrent chemotherapy Q3W (platinum- and nonplatinum-based regimens) in patients with nonmyeloid malignancies (40% breast cancer). Primary endpoints were mean change in hemoglobin after 6 weeks from baseline and proportion of patients with hemoglobin increase from baseline were 1 g/dL. Secondary endpoints at the entire treatment period (16 weeks) were the proportion of patients with hemoglobin increase of hemoglobin >2 g/ dL or a level of >12 g/dL in the absence of RBC transfusion, time to erythropoietic response, proportion of patients who had a RBC transfusion from week 5 to end of treatment. The overall erythropoietic response was 74%, and there was no difference between groups in the proportion of patients who achieved an increase in hemoglobin equal to or >1 g/ dL, and time to erythropoietic response. Only 19% of patients required transfusion support. These results seem to be comparable with those obtained with darbepoetin QW administration. Two data suggest that the binding to receptor plays a role in the clearance of EPS in patients with chemotherapy-induced anemia: a) pharmacokinetic analysis Therapeutics and Clinical Risk Management 2007:3(2)