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Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients

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Abstract

Purpose

To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation.

Methods

Data from 41 subjects receiving cyclophosphamide, thiotepa and carboplatin were used to develop the ANC model consisting of a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments. PBSC were incorporated into the first transit compartment following a zero-order process, k in , and the rebound effect was explained by a feedback mechanism. A ‘kinetics of drug action’ model was used to quantify the HDC effect on the progenitor cells according to a linear function, with a slope (α).

Results

The typical of the ANC at baseline (Circ 0 ), mean transit time (MTT), feedback parameter (γ), k in and α were estimated to be 5,610·106/L, 3.25 days, 0.145, 0.954 cell/kg/day and 2.50 h/U, respectively. rHuG-CSF shortens the MTT by 92% and increases the mitotic activity by 120%. Bootstrap analysis, visual predictive check and numerical predictive checks evidenced accurate prediction of the ANC nadir, time to ANC nadir and time to grade 4 neutropenia recovery.

Conclusion

The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted. Higher amount of CD34+ cells in the PBSC transplantation and earlier administration rHuG-CSF were associated with faster haematological recovery.

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ACKNOWLEDGEMENTS

The authors would like to thank the patients, investigators (Dra. Ana Lluch and Dr. Daniel Almenar) and their medical, nursing and laboratory staff who participated in the study. In addition, the authors recognize the valuable comments provided by Dr. N. Victor Jimenez and Dr. Vicente G. Casabó at the beginning of the analysis.

Conflict of Interest

This study was supported by Grant 97/0758 from Fondo de Investigaciones Sanitarias, Ministerio de Sanidad (Spain). The authors disclosure none conflict of interest other than Juan Jose Perez Ruixo is AMGEN employee since May 2007.

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Authors and Affiliations

  1. Pharmacy and Pharmaceutics Division, Department of Engineering, Miguel Hernandez University, San Juan de Alicante, Alicante, Spain

    Amelia Ramon-Lopez, Ricardo Nalda-Molina, Belen Valenzuela & Juan Jose Perez-Ruixo

  2. C/ Picayo, 3, 46530, Puzol, Valencia, Spain

    Juan Jose Perez-Ruixo

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  1. Amelia Ramon-Lopez
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  2. Ricardo Nalda-Molina
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Correspondence to Juan Jose Perez-Ruixo.

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Ramon-Lopez, A., Nalda-Molina, R., Valenzuela, B. et al. Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients. Pharm Res 26, 1952–1962 (2009). https://doi.org/10.1007/s11095-009-9910-6

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