Pharmacodynamics of Darbepoetin Alfa in Patients

Clinical studies with darbepoetin alfa have been conducted in the United States, European Union, Australia, Canada, and Mexico. Several studies in the nephrology setting showed that darbepoetin alfa was effective at correcting anemia at a reduced dosing frequency. Randomized dose escalation studies compared once-weekly darbepoetin alfa (0.45 Mg/kg) with twice-weekly rHuEPO (50 U/kg) in rHuEPO-naive predialysis patients (123). Drug dosages were adjusted, as necessary, to maintain Hb concentrations in the study target range (11-13 g/dL). In both treatment groups there was a significant Hb response (mean Hb increase of 1.38 g/dL for darbepoetin alfa and 1.4 g/dL for rHuEPO. Similar proportions of the patients achieved an Hb response of 1 g/dL or greater from baseline by 24 wk, 93% of the 129 patients treated with darbepoetin alfa and 92% of the 37 patients treated with rHuEPO.

Conversion of dialysis patients from established rHuEPO therapy to darbepoetin alfa was addressed in two large clinical trials. In both studies the safety profiles of the rHuEPO and darbepoetin alfa groups was similar. The first trial, in North America, enrolled 507 hemodialysis patients into a randomized double-blind study, comparing patients who continued on three-times-weekly rHuEPO with those converting to darbepoetin alfa (once weekly plus twice-weekly placebo) (124). After the 20-wk dose-titration phase, Hb concentration remained stable during the 8-wk follow-up phase and was comparable between the two groups. The second clinical trial, a European/Australian multicenter study, included hemodialysis and peritoneal dialysis patients who were randomized to darbepoetin alfa administered at either weekly intervals (if prior rHuEPO was given two or three times weekly) or at every-other-week dosing intervals (if prior rHuEPO dosing was weekly). The results suggested that that 97% of patients receiving weekly darbepoetin alfa and 95% of those on an alternate-week schedule could be successfully treated.

The ability of darbepoetin alfa to maintain Hb concentrations at reduced dosing intervals was evaluated in several clinical studies. Seventy-six rHuEPO-naive patients with chronic kidney disease (61 completed the treatment phase) were administered darbepoetin alfa at an every-two-weeks (q2w) dosing interval, and 97% reached the target Hb concentration Therefore darbepoetin administration could be used to treat anemia at every-other-week dosing intervals. Similarly, darbepoetin alfa administered to dialysis patients at q2w dosing intervals successfully maintained Hb concentrations in patients converted from rHuEPO. Hemoglobin was also successfully maintained in dialysis patients with darbepoetin alfa at even less frequent dosing intervals, q3w and q4w. Therefore it appears that darbepoetin alfa can be administered at less frequent intervals than rHuEPO.

Patients with cancer often have anemia caused by the inhibitory effects of the tumor, (inflammatory cytokines, destruction of bone marrow, bleeding) or anticancer treatment (chemotherapy or radiotherapy). The anemia can have profound negative effects on well-being and survival (125). The efficacy of darbepoetin alfa antianemia treatment was demonstrated in cancer patients not receiving chemotherapy (125). Patients, 102 primarily with lymphoid, breast, and prostate malignancies, were administered from 1.0 to 4.5 ^.g/kg/wk and studied for 12 wk. A 2-g/dL increase in Hb was observed in 66% or more of the patients. The 4.5-^g/kg/wk group had an even higher (92%) response rate.

Darbepoetin alfa has also been shown to treat anemia in a safe and effective manner in cancer patients receiving chemotherapy. In a multicenter, placebo-controlled study, patients with lung cancer receiving multicycle chemotherapy were randomized to darbepoetin alfa or placebo, and patients who completed the 28-wk study were assessed (126). Patients treated with darbepoetin alfa required fewer transfusions (and had greater Hb responses) than patients receiving placebo. Other studies have suggested that darbepoetin alfa is safe and effective when administered at reduced dosing frequency (once every 1, 2, or 3 wk) (125,127-129). Thus, darbepoetin alfa could be used to treat anemia in patients with reduced-dosing frequency.

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