Melhem 2017 - Neutropenia Model

Model Identifier

MODEL2211040001

Short description

The objective of the present study was to use pharmacokinetic–pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia

Format

SBML (L3V2)

Related Publication

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.
Melhem M, Delor I, Pérez-Ruixo JJ, Harrold J, Chow A, Wu L, Jacqmin P
British journal of clinical pharmacology , 5/ 2018 , Volume 84 , Issue 5 , pages: 911-925 , DOI: 10.1111/bcp.13504

Affiliation: Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., Thousand Oaks, CA, USA.

Abstract:

Aim

The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim.

Methods

Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production.

Results

The systemic half-lives of filgrastim (2.6 h) and pegfilgrastim (10.1 h) were as expected. The effective half-life of chemotherapy was 9.6 h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model.

Conclusion

This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

Contributors

Submitter of the first revision: Shiny MARTIS B
Submitter of this revision: Shiny MARTIS B
Curator: Shiny MARTIS B

Metadata information

hasProperty (1 statement)

OTHER

Curation status

Non-curated

Modelling approach(es)

Other

Connected external resources

SBGN view in Newt Editor

Name	Description	Size	Actions
Model files (1)
Neutropenia.xml	SBML L3V2 representation of the Nutropenia model	37.06 KB	Preview \| Download

Model originally submitted by : Shiny MARTIS B
Submitted: Nov 4, 2022 12:22:34 PM
Last Modified: Nov 4, 2022 12:22:34 PM

Revisions

Version: 1
- Submitted on: Nov 4, 2022 12:22:34 PM
- Submitted by: Shiny MARTIS B
- With comment: Import of Melhem 2017 - Neutropenia Model