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Population Modeling of Filgrastim PK‐PD in Healthy Adults Following Intravenous and Subcutaneous Administrations
Author(s) -
Krzyzanski Wojciech,
Wiczling Pawel,
Lowe Phil,
Pigeolet Etienne,
Fink Martin,
Berghout Alexander,
Balser Sigrid
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010376966
Subject(s) - medicine , filgrastim , population , anesthesia , pharmacology , neutropenia , chemotherapy , environmental health
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.