Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia - A phormacokinetic and pharmacodynamic investigation

In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions I month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin <= 12.5 g/dL) in 2 randomized, double-blind, placebo-controlled studies. Subcutaneous (SC) and intravenous administration of 0.75 mu g/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 mu g/kg SC doses with placebo. Darbepoetin alfa (0.75 mu g/kg SC) pharmacokinetics were similar in CHF patients and healthy subjects, with a mean (+/- SD) bioavailability of 29 (+/- 11)% and 37 (+/- 8)%, respectively. In anemic CHF patients, mean ( SD) increases in hemoglobin at 4 weeks after the second monthly dose of 2.0, 3.0, and 5.0 mu g/kg (SC) of darbepoetin alfa were 2.3 (+/- 0.6), 1.4 (+/- 1.0), and 2.4 (+/- 1.9) g/dL, respectively. Darbepoetin alfa 0.75 mu g/kg (SC) given twice, I month apart, was insufficient to increase hemoglobin in this study. No severe, drug-related adverse events occurred. Darbepoetin alfa administered once monthly elevates and maintains the hemoglobin concentration in patients with CHF and anemia.