The Absorption of Darbepoetin Alfa Occurs Predominantly via the Lymphatics Following Subcutaneous Administration to Sheep
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To determine the contribution of the lymphatics to the systemic availability of darbepoetin alfa (DA) using an established sheep model.
Materials and Methods
DA was administered either by intravenous (IV) injection (0.2, 0.5 or 2 μg/kg) or by subcutaneous (SC) administration (2 μg/kg) into the interdigital space of the hind leg. A SC control group was used to determine the absolute bioavailability (F sys). Cannulation of the peripheral lymphatics in a parallel SC group allowed the continuous collection of lymph draining the injection site and determination of the cumulative amount of DA absorbed via the lymphatics. Serum and lymph concentrations of DA were determined by ELISA. The fraction of the dose absorbed into the lymphatics (F lymph) relative to the fraction absorbed directly into the blood (F blood) was determined using a compartmental approach.
Dose-linear pharmacokinetics was observed within the dose range investigated. The bioavailability was virtually complete following SC injection into the interdigital space (88.4 ± 15.7%). A high proportion of the administered dose was recovered in peripheral lymph (90.2 ± 4.4%) resulting in a substantial reduction in the systemic availability in lymph cannulated animals (3.7%).
The high recovery of DA in the peripheral lymph demonstrated near complete absorption of this recombinant protein via the lymphatics in a lymph cannulated sheep model.
Key wordsdarbepoetin alfa lymph protein delivery protein pharmacokinetics subcutaneous injection
The technical assistance of Ms. Majella Snelling is gratefully acknowledged. Financial support for this study was provided by Amgen Inc., Thousand Oaks, California.
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