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Pharmacokinetics of Novel Erythropoiesis Stimulating Protein Compared with Epoetin Alfa in Dialysis Patients

IAIN C. MACDOUGALL^*, STEPHEN J. GRAY, ORLAITH ELSTON^*, CORMAC BREEN^*, BARBARA JENKINS, JEFF BROWNE and JOAN EGRIE

^* Department of Renal Medicine, King's College Hospital, London, United Kingdom
Amgen Limited, Cambridge, United Kingdom
Amgen, Inc., Thousand Oaks, California.

Correspondence to Dr. Iain C. Macdougall, Renal Unit, King's College Hospital, East Dulwich Grove, London SE22 8PT, United Kingdom. Phone: +44 171 346 6234; Fax No: +44 171 346 6472; E-mail: icm-kru{at}globalnet.co.uk

Abstract. Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration—time curve was significantly greater for NESP (291.0 ± 7.6 ng · h per ml versus 131.9 ± 8.3 ng · h per ml; mean ± SEM; P < 0.0005), and clearance was significantly lower (1.6 ± 0.3 ml/h per kg versus 4.0 ± 0.3 ml/h per kg; mean ± SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 ± 2.0 ml/kg versus 48.7 ± 2.1 ml/kg; mean ± SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.

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