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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 1 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 μg/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 μg/kg SC doses with placebo. Darbepoetin alfa (0.75 μg/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 μg/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 μg/kg (SC) given twice, 1 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.