Pharmacokinetics of Darbepoetin Alfa after Intravenous or Subcutaneous Administration in Patients with Non-myeloid Malignancies Undergoing Chemotherapy

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Abstract
The pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was to evaluate the pharmacokinetics of IV or subcutaneous (SC) darbepoetin alfa in patients with non-myeloid malignancies undergoing multicycle chemotherapy. Fifty-six patients (haemoglobin <13.0 g/dL) received weekly darbepoetin alfa 2.25 µg/kg administered either IV (n = 27) or SC (n = 29) during up to three cycles of chemotherapy. Noncompartmental pharmacokinetic analysis was performed, including analysis of intensive pharmacokinetic profiles collected over 168 hours during week 1 of both the first and third cycles of chemotherapy. Darbepoetin alfa serum concentrations exhibited a biphasic profile (a rapid distributive phase followed by a slower terminal elimination phase) after IV administration, whereas darbepoetin alfa was slowly absorbed after SC administration. Darbepoetin alfa exhibited limited extravascular distribution after IV administration, with both initial and steady-state mean volumes of distribution (36.1 mL/kg and 55.2 mL/kg, respectively, after a single IV dose) approximating the plasma volume. After a single IV dose, darbepoetin alfa exhibited a mean clearance of 1.05 mL/h/kg, with a mean terminal half-life of 38.8 hours. Similar pharmacokinetic results were observed after single and multiple doses of darbepoetin alfa, for both SC and IV administration. Darbepoetin alfa is cleared slowly after IV administration to patients with cancer receiving chemotherapy, resulting in a terminal half-life of 38.8 hours. No evidence of accumulation and no changes in pharmacokinetic profiles after repeated administration were observed in cancer patients undergoing cyclic chemotherapy, for both IV and SC dosing.