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DDMODEL00000077: Krzyzanski_2010_Filgastrim_PKPD

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Short description:
Model comprised of files: Executable_simulated_GCSF_dataset.ctl, Output_real_GCSF.lst, Output_simulated_GCSF_dataset.lst, Command.txt, Simulated_GCSF_dataset.csv
Original code
  • Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations.
  • Krzyzanski W, Wiczling P, Pigeolet E, Fink M, Berghout A, Balser S
  • Journal of clinical pharmacology, 9/2010, Volume 50, pages: 101S-112S
  • (1) Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA. (2) Modeling and Simulation Novartis Pharma AG (3) Sandoz Biopharmaceutical Development
  • 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.
Celine Sarr
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  • Model owner: Celine Sarr
  • Submitted: Dec 9, 2015 10:04:05 AM
  • Last Modified: May 23, 2016 12:56:50 PM
  • Version: 6 public model Download this version
    • Submitted on: May 23, 2016 12:56:50 PM
    • Submitted by: Celine Sarr
    • With comment: Updated model annotations.
  • Version: 2 public model Download this version
    • Submitted on: Dec 9, 2015 10:04:05 AM
    • Submitted by: Celine Sarr
    • With comment: Edited model metadata online.