Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G‐CSF mutant (Ro 25‐8315) in healthy volunteers: Comparison with single and multiple daily doses of filgrastim

Abstract Ro 25‐8315 is produced by conjugation of rhG‐CSF mutant with polyethylene glycol (PEG). The purpose of this study was to examine the pharmacodynamics and pharmacokinetics of Ro 25‐8315 in comparison with Filgrastim (rhG‐CSF). Subjects received single subcutaneous doses of Ro 25‐8315 ranging from 10 to 150 μg/kg using a double‐blind, randomized, placebo‐controlled design. Filgrastim was administered as a single dose (5 or 10 μg/kg) and, following a 14‐day washout period, daily for 7 days. Ro 25‐8315 increased absolute neutrophil count (ANC) by 6‐ to 8‐fold and CD34 + cell count more than 30‐fold at the highest doses tested. Single doses (60–150 μg/kg) of Ro 25‐8315 and multiple doses of Filgrastim had similar effects on ANC and CD34 + , although Ro 25‐8315 had a greater effect on CFU‐GM. The pharmacokinetics of Ro 25‐8315 were dose‐dependent, with peak concentrations and area under the serum concentration–time curve (AUC) increasing 100‐fold over the range of doses studied. Time to reach peak concentration ( T max ) and half‐life of Ro 25‐8315 averaged 20–30 hr at all doses, approximately three times longer than with Filgrastim. Adverse events were not serious and occurred with similar frequency with both products. Pegylation of rhG‐CSF mutant results in more desirable pharmacokinetic properties and a longer duration of action with effective increases in ANC and measures of peripheral blood progenitor cell mobilization for at least 1 week. Am. J. Hematol. 66:245–251, 2001. © 2001 Wiley‐Liss, Inc.