title: Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.
abstract: The covalent attachment of polyethylene glycol to filgrastim results in a new molecule pegfilgrastim, which has a significantly longer half-life than filgrastim. It is likely that the clearance of both filgrastim and pegfilgrastim involves granulocyte colony simulating factor (G-CSF) receptor binding, but the pharmacokinetics of these drugs have not been compared in mice with and without a functional G-CSF receptor. We sought to clarify the role of receptor-mediated clearance of filgrastim and pegfilgrastim using wild-type (WT) mice or mice with a non-functional G-CSF-R (knockout, KO). We administered single doses of filgrastim or pegfilgrastim (10 or 100 microg kg(-1)) intravenously to WT and KO mice. Plasma levels of protein were measured by enzyme-linked immunosorbent assay (ELISA) at preset time points, and AUC, MRT, CL, V(d), and T(1/2) were calculated. When compared with WT mice, the G-CSF-R KO mice had significantly greater AUC, longer MRT, longer T(1/2), and lower clearance. This was the case whether animals received 10 or 100 microg kg(-1) and whether they received filgrastim or pegfilgrastim. The volume of protein distribution was identical among WT and KO mice. However, the V(d) was larger after pegfilgrastim dosing than after filgrastim dosing. In both WT and KO mice, increasing the dose of figrastim or pegfilgrastim resulted in a proportional increase in the AUC. A functional G-CSF-R is an important mechanism in the plasma clearance of both filgrastim and pegfilgrastim.
authors.affiliation: All Children's Hospital, Children's Research Institute, University of South Florida, 140 Seventh Avenue South CRI Room 2006, St. Petersburg, FL 33701, USA.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Kotto-Kome
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Fox
authors.forename: Wenge
authors.initials: W
authors.lastname: Lu
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Yang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Christensen
authors.forename: Darlene A
authors.initials: DA
authors.lastname: Calhoun
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004797:Enzyme-Linked Immunosorbent Assay; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics*; D006207:Half-Life; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011092:Polyethylene Glycols; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000493:pharmacokinetics
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000069585:Filgrastim