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Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach

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Abstract

Background

Granulocyte colony‐stimulating factors (G‐CSF) are commonly given to limit chemotherapy‐induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical.

Objectives

This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G‐CSF regimens on neutropenia’s incidence for patients treated by eribulin, to propose an optimal G‐CSF dosing schedule.

Methods

A population PK/PD model was developed to describe absolute neutrophil counts’ (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G‐CSF. Final model estimates were used to calculate neutropenia’s incidence following different G‐CSF dosing schedules for 1000 virtual subjects.

Results

The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G‐CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia.

Conclusion

Simulations showed a single G‐CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin‐induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence.

Trial registration

NCT02841722.

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Data availability

Data available on request to the authors.

Code availability

Code available on request to the authors.

Change history

  • 13 August 2022

    The original version is revised due to the update of new trial ID.

Abbreviations

ALAT:

Alanine aminotransferase

ASAT:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

ANC:

Absolute neutrophil count

BSA:

Body surface area

EM:

Expectation maximization

G-CSF:

Granulocyte colony-stimulating factor

\(\gamma\)GT:

γ-Glutamyl transferase

MBC:

Metastatic breast cancer

MTT:

Mean transit time

OFV:

Objective function value

PK/PD:

Pharmacokinetic/pharmacodynamic

RSE:

Relative standard error

pcVPC:

Prediction corrected visual predictive checks

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Funding

This work was supported by Eisai. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Manon Reda and Pauline Macaire contributed equally to this work.

Authors and Affiliations

  1. Oncology Department, Centre Georges-François Leclerc, Dijon, France

    Manon Reda, Hélène Bellio, Silvia Ilie, Véronique Lorgis, Audrey Hennequin, Sylvain Ladoire, Pierre Fumoleau, Nicolas Isambert & Isabelle Desmoulins

  2. Pharmacy Department, Centre Georges-François Leclerc, 1 rue Pr Marion, 21079, Dijon, France

    Pauline Macaire, Sylvain Ladoire & Antonin Schmitt

  3. INSERM U1231, University of Burgundy Franche-Comté, Dijon, France

    Pauline Macaire & Antonin Schmitt

  4. Oncology Department, Institut de Cancérologie de Lorraine, Alexis Vautrin, Vandœuvre-lès-Nancy, France

    Lionel Uwer

  5. Department of Epidemiology and Biostatistics, Georges François Leclerc Center, Dijon, France

    Emilie Rederstorff

  6. Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Université Claude Bernard Lyon 1, GINECO, Lyon, France

    Nathalie Bonnin, Benoit You & Gilles Freyer

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  1. Manon Reda
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Corresponding author

Correspondence to Antonin Schmitt.

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Conflict of interest

Gilles Freyer declares having to participate in a symposium organized by Eisai. All the other authors have no conflict of interest.

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Comité de Protection des Personnes Grand Est I (Approval Number CPP 2015/14). Each patient provided written informed consent to participate.

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Reda, M., Macaire, P., Bellio, H. et al. Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach. Cancer Chemother Pharmacol 89, 197–208 (2022). https://doi.org/10.1007/s00280-021-04395-y

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