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An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity

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Abstract

Purpose

Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity.

Methods

Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE100C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC).

Results

Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3 kg. LBM was associated with neutrophil nadir (r = 0.5, P = 0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2 kg, P = 0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC.

Conclusion

To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.

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Acknowledgments

We thank Laura Birdsell for her assistance with body composition analysis, Linda Harris for her bibliographic expertise, Edith Pituskin, Sambasivarao Damaraju, Andrew G. Scarfe, Mark Clemons, Katia Tonkin, Heather-Jane Au, Sheryl Koski, Anil A. Joy, Michael Smylie, Karen King and Diana Carandang for their assistance with data collection. Roche Fellowship in Translational Research from Alberta Cancer Foundation (CMMP), Alberta Heritage Foundation for Medical Research (AHFMR) Fellowship (CMMP), Canadian Breast Cancer Research Alliance (MBS), Alberta Cancer Foundation (ACF) and Canadian Institute of Health Research (MBS). The authors had full control of all primary data and agree to allow the journal to review the data if requested. M. B. Sawyer—Research and Travel (ASCO) Funding from Pfizer Oncology, J. R. Mackey—Honoraria from Pfizer Oncology.

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Authors and Affiliations

  1. Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada

    Carla M. M. Prado, Vickie E. Baracos, Tony Reiman, John R. Mackey, Michelle Kuzma, Vijaya L. Damaraju & Michael B. Sawyer

  2. Public Health Sciences, University of Alberta, Edmonton, AB, Canada

    Isac S. F. Lima

  3. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

    Robert R. Bies

  4. Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB, Canada

    Linda J. McCargar

Authors
  1. Carla M. M. Prado
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  2. Isac S. F. Lima
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  3. Vickie E. Baracos
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  5. Linda J. McCargar
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  8. Michelle Kuzma
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  9. Vijaya L. Damaraju
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  10. Michael B. Sawyer
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Corresponding author

Correspondence to Michael B. Sawyer.

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Prado, C.M.M., Lima, I.S.F., Baracos, V.E. et al. An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity. Cancer Chemother Pharmacol 67, 93–101 (2011). https://doi.org/10.1007/s00280-010-1288-y

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  • DOI: https://doi.org/10.1007/s00280-010-1288-y

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