Darbepoetin Alfa

Darbepoetin alfa (Aranesp®, Nespo®) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses.

Darbepoetin alfa is generally well tolerated, and clinical trials of 20–52 weeks’ duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks’ duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

A glycosylated polypeptide chain, EPO has four attached carbohydrate chains, each terminated by a number of negatively charged sialic acid molecules. Darbepoetin alfa is an analog of rhEPO containing five amino acid substitutions that increase the maximum number of sialic acid residues from 14 to 22. These extra sialic acid residues permit receptor binding and the induction of downstream intracellular signaling pathways, but the relative affinity for the EPO-receptor is lower than that of rhEPO.

The reduced affinity of darbepoetin alfa appears to retard EPO-receptor-mediated removal of darbepoetin alfa, increase mean terminal elimination half-life (t1/2β), and reduce clearance. The increase in circulating half-life is sufficient to overcome the decline in affinity for the EPO receptor, as reflected by a greater biological activity than rhEPO. In dialysis patients, intravenous or subcutaneous darbepoetin alfa once or three times per week increased mean Hb levels by ≥1 g/dL in 60–80% of patients after 4 weeks.

Absorption of darbepoetin alfa after subcutaneous administration is slow relative to intravenous administration, while elimination is prolonged in comparison with epoetin alfa. The volume of distribution of a single intravenous dose of darbepoetin alfa in patients with CKD was 47–64 mL/kg, approximating plasma volume. After subcutaneous administration of darbepoetin alfa 0.5 or 1 μg/kg, the mean maximum serum concentration of 0.94 or 2.62 mg/mL was reached in a mean of 54 or 36 hours, the area under the concentration-time curve from time zero to infinity was 108 or 305 ng · h/mL, and mean bioavailability was 37%.

Mean t1/2β after a single intravenous dose of darbepoetin alfa was ≈3-fold longer than that of rhEPO (13.1–25.3 vs 6.3–8.5 hours) and clearance was 50–60% slower (1.6–2.1 vs 4.0–8.6 mL/h/kg). Subcutaneous administration prolonged the mean t1/2β to 70 hours and increased clearance to 3.5 mL/h/kg.

Repeated intravenous administration once or three times per week for up to 12 weeks did not produce major changes in clearance or volume of distribution. The pharmacokinetic profile in children with CKD (aged 3–16 years) was generally similar to that in adults.

Subcutaneous or intravenous darbepoetin alfa, whether administered at 1- or 2-week intervals, successfully induced erythropoiesis in ≥93% of patients not yet on dialysis and 72% of patients undergoing hemodialysis or peritoneal dialysis. The mean Hb level in these patients increased by 1.1–2.4 g/dL in 20- to 52-week trials.

Darbepoetin alfa was also effective in the maintenance of established erythropoiesis after conversion from rhEPO to darbepoetin alfa therapy in CKD patients not yet on dialysis and in those on dialysis. In addition, therapy with darbepoetin alfa at 2-week intervals was noninferior to therapy at 1-week intervals in maintaining stable Hb levels established during darbepoetin alfa treatment once per week, while the majority of dialysis patients receiving darbepoetin alfa treatment at 3- or 4-week intervals maintained Hb levels ≥10 g/dL for up to 40 weeks.

Darbepoetin alfa was generally well tolerated in 20- to 52-week trials and, while adverse events were reported by 83–98% of darbepoetin alfa and 65–100% of rhEPO recipients, most were of mild-to-moderate severity. In addition, the incidences of adverse events of any severity were generally lower in darbepoetin alfa than rhEPO recipients.

The incidences of six events (hypertension, thrombosis of vascular access, acute myocardial infarction, cerebrovascular disorders, seizures, and transient ischemic attack) considered of particular importance in patients with CKD were similar in darbepoetin alfa and rhEPO treatment groups. Iron deficiency was common and necessitated supplementary iron administration in ≥76% of patients.

Serious adverse events occurred with similar incidences in darbepoetin alfa and other rhEPO recipients, and deaths occurred in 1–12% of darbepoetin alfa and 3–7% of rhEPO recipients, although most were attributed to comorbid conditions, particularly cardiovascular disease, and were not considered related to study drugs.