DDMODEL00000077: Krzyzanski_2010_Filgastrim_PKPD

  public model
Short description:
a PK-PD model for G-CSF combining the receptor-mediated PK model with a PD model of neutrophil dynamics
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. wk@buffalo.edu (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
Context of model development: Mechanistic Understanding;
Long technical model description: The free G-CSF concentration C in the serum was assumed to be in an instantaneous equilibrium with the bone marrow and to bind to G-CSF receptors R present on blood and bone marrow neutrophils , to form drug receptor complex. The G-CSF can also be directly eliminated by a glomerular filtration and subsequent renal metabolism. The drug receptor complex can dissociate or be internalized . The internalized G-CSF receptor complex was assumed to be further degraded in the endosomes and not to recycle as a free receptor and a drug molecule. the identification of the binding parameters in the presence of the PD data was difficult, the TMDD model of G-CSF disposition was further reduced to a rapid binding form where the free drug and receptor concentrations are replaced by total concentrations because of the quasi-equilibrium assumption. The total number of receptor is assumed to be proportional to the number of neutrophils in the bone marrow and the blood. The development of neutrophil precursor cells in the bone marrow was described by a sequence of n = 9 transit compartments with a transit rate constant. For parsimony reasons, the same potency parameter, SC50 (drug serum concentration eliciting 50% of the maximum effect), was used for the G-CSF effect on cell proliferation and cell maturation. 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. Simultaneous modeling of filgrastim plasma concentrations and ANC was necessary to adequately describe PK data. Simulations with varying PK and PD parameter values indicated that the presented model could be used for data of other granulopoiesis stimulating agents. ;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: a pharmacokinetic (PK) and pharmacodynamic (PD) model was develop to account for an increase in G-CSF clearance on multiple dosing because of an increase of the G-CSF receptor-mediated endocytosis;
Modelling task in scope: estimation;
Nature of research: Life cycle management;
Therapeutic/disease area: Oncology;
Annotations are correct.
This model is not certified.
  • Model owner: Celine Sarr
  • Submitted: Dec 9, 2015 10:04:05 AM
  • Last Modified: May 23, 2016 12:56:50 PM
Revisions
  • 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.
 
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