title: Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations.
abstract: Filgrastim is a recombinant human granulocyte colony stimulating factor (G-CSF) that stimulates production of neutrophils. The objective of this analysis was to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model to account for an increase in G-CSF clearance on multiple dosing because of an increase of the G-CSF receptor-mediated endocytosis. Data from 4 randomized studies involving healthy volunteers were used for analysis. Subjects received filgrastim (Neupogen) via subcutaneous (SC) and intravenous (IV) routes. Filgrastim was administered SC daily for 1 week at 2.5, 5, and 10 µg/kg doses and as single IV infusions (5 µg/kg over 0.5 hours) and SC (1 µg/kg) doses. PK data comprised serum concentration-time measurements and the blood absolute neutrophil count (ANC) was used for PD evaluations. Population nonlinear mixed-effect modeling was done using NONMEM VI (Version 6.1.0, Icon Development Solutions, Ellicott City, Maryland). The model depicted the decaying trend in C(max) values with repeated doses and an increase in ANC(max) values consistently with an increase in the G-CSF receptor pool. Simulated time courses of the total clearance exhibited an increasing pattern. The increase in filgrastim clearance on multiple dosing was attributed to the increased neutrophil count in the bone marrow and blood paralleled by an increase in the total G-CSF receptor density.
authors.affiliation: Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA. wk@buffalo.edu
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
authors.forename: Pawel
authors.initials: P
authors.lastname: Wiczling
authors.forename: Phil
authors.initials: P
authors.lastname: Lowe
authors.forename: Etienne
authors.initials: E
authors.lastname: Pigeolet
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Alexander
authors.initials: A
authors.lastname: Berghout
authors.forename: Sigrid
authors.initials: S
authors.lastname: Balser
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D017711:Nonlinear Dynamics; D016032:Randomized Controlled Trials as Topic; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D011994:Recombinant Proteins; D055815:Young Adult
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim