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

Ro 25-8315 is produced by conjugation of rhG-CSF mutant with polyethylene g lycol (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 mug/kg using a double-blind, randomized, placebo-controlled design, Filgrastim was administered as a single dose (5 or 10 mug/kg) and, followin g a 14-day washout period, daily for 7 days, no 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 mug/kg) of no 25-831 5 and multiple doses of Filgrastim had similar effects on ANC and CD34(+), although no 25-8315 had a greater effect on CFU-GM. The pharmacokinetics of no 25-8315 were dose-dependent, with peak concentrations and area under th e serum concentration-time curve (AUC) increasing 100-fold over the range o f 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 si milar 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. ( C) 2001 Wiley-Liss, Inc.