Population Modeling of Filgrastim PK-PD in Healthy Adults Following Intravenous and Subcutaneous Administrations

• Published in: Journal of clinical pharmacology Vol. 50; no. S9; pp. 101S - 112S
• Main Authors: Krzyzanski, Wojciech, Wiczling, Pawel, Lowe, Phil, Pigeolet, Etienne, Fink, Martin, Berghout, Alexander, Balser, Sigrid
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2010; SAGE Publications; Wiley Subscription Services, Inc
• Subjects: Adult; Dose-Response Relationship, Drug; Female; Filgrastim; Granulocyte Colony-Stimulating Factor - administration & dosage; Granulocyte Colony-Stimulating Factor - pharmacokinetics; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte-colony stimulating factor; granulopoiesis; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; mechanistic models; Middle Aged; Models, Biological; neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Nonlinear Dynamics; Randomized Controlled Trials as Topic; Receptors, Granulocyte Colony-Stimulating Factor - metabolism; Recombinant Proteins; target-mediated drug disposition; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270010376966

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 Cmax values with repeated doses and an increase in ANCmax 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.