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Population Pharmacokinetics and Pharmacodynamics of Doxorubicin and Cyclophosphamide in Breast Cancer Patients

A Study by the EORTC-PAMM-NDDG

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Abstract

Aims

To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.

Patients and methods

Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m2 over 15 minutes followed by cyclophos-phamide 600 mg/m2 over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response.

Results

Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 μmol ∙ h/L [95% CI 889, 1001] vs 602 μmol ∙ h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance.

Conclusions

The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.

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Acknowledgements

This study was part of the Biomed Project: Population Pharmacokinetic/Pharmacodynamic Analysis of Anticancer Drug Treatment (PL96-2333). The coordinator was Jan Schellens. The study was performed on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-Pharmacology and Molecular Mechanisms Group (PAMM) and New Drug Development Group (NDDG). Markus Joerger is supported by a fellowship grant funded by the European Society of Medical Oncology and by a research grant from the Swiss National Science Foundation (PBBSB-102331). The project was supported by a grant from the European Community (Biomed Project PL 96-2333). The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands

    Markus Joerger, Alwin D. R. Huitema & Jos H. Beijnen

  2. Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands

    Markus Joerger, Jos H. Beijnen & Jan H. M. Schellens

  3. Medical Spectrum Twente, Enschede, The Netherlands

    Dick J. Richel

  4. Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) and Applied Cancer Research-Institute for Translational Research (ACR-ITR VIEnna), Kaiser-Franz-Josef Hospital, Vienna, Austria

    Christian Dittrich

  5. Ioannina University Hospital, Ioannina, Greece

    Nikolas Pavlidis & Evangelos Briasoulis

  6. University Hospital Antwerp, Edegem, Belgium

    Jan B. Vermorken

  7. University of Bologna, Bologna, Italy

    Elena Strocchi

  8. Policlinico S. Orsola-Malpighi, Bologna, Italy

    Andrea Martoni

  9. National Cancer Institute, Aviano, Italy

    Roberto Sorio

  10. Leyenburg Hospital, Den Haag, The Netherlands

    Henk P. Sleeboom

  11. Catalan Institute of Oncology, Barcelona, Spain

    Miguel A. Izquierdo

  12. University of Edinburgh, Edinburgh, UK

    Duncan I. Jodrell

  13. Centre R. Gauducheau, Saint Herblain, France

    Régine Féty

  14. UZ Gasthuisberg, Leuven, Belgium

    Ernst de Bruijn

  15. University of Münster, Münster, Germany

    Georg Hempel

  16. Uppsala University, Uppsala, Sweden

    Mats Karlsson

  17. Leon Berard Centre, Lyon, France

    Brigitte Tranchand

  18. Lyon University, Lyon, France

    Brigitte Tranchand

  19. Faculty of Medicine Lyon Sud, EA3738, Ciblage Thérapeutique en Oncologie, Oullins, France

    Brigitte Tranchand

  20. European Organisation for Research and Treatment of Cancer-New Drug Development Group, Brussels, Belgium

    Ad H. G. J. Schrijvers

  21. Bradford NHS Trust & Beatson Oncology Centre, University of Leeds, Glasgow, UK

    Chris Twelves

  22. Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

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  1. Markus Joerger
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  2. Alwin D. R. Huitema
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  8. Elena Strocchi
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  10. Roberto Sorio
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  11. Henk P. Sleeboom
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  12. Miguel A. Izquierdo
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  13. Duncan I. Jodrell
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  14. Régine Féty
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  15. Ernst de Bruijn
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  16. Georg Hempel
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  17. Mats Karlsson
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  18. Brigitte Tranchand
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  19. Ad H. G. J. Schrijvers
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  20. Chris Twelves
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  21. Jos H. Beijnen
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  22. Jan H. M. Schellens
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Corresponding author

Correspondence to Markus Joerger.

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Joerger, M., Huitema, A.D.R., Richel, D.J. et al. Population Pharmacokinetics and Pharmacodynamics of Doxorubicin and Cyclophosphamide in Breast Cancer Patients. Clin Pharmacokinet 46, 1051–1068 (2007). https://doi.org/10.2165/00003088-200746120-00005

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  • DOI: https://doi.org/10.2165/00003088-200746120-00005

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