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Determination of clinically therapeutic endoxifen concentrations based on efficacy from human MCF7 breast cancer xenografts

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Abstract

Tamoxifen is a widely prescribed adjuvant anti-estrogen agent for estrogen receptor-positive breast cancer. Tamoxifen is known to undergo CYP2D6-mediated bioactivation to the active metabolite endoxifen. Endoxifen concentrations exhibit high interindividual variability, contributing to either sub-optimal tamoxifen efficacy or side effects in subsets of patients. However, the relationship between endoxifen exposure and tumor growth inhibition has not been well-characterized and little is known regarding the optimal in vivo endoxifen plasma level required for tumor inhibition. Pharmacokinetics–Pharmacodynamics (PK–PD) modeling was carried out to characterize the relationship between endoxifen concentration and tumor growth inhibition (TGI) in dose-ranging experiments in the human MCF7 xenograft bearing mouse model. Subsequently, simulations using human PK were used to determine the efficacious clinically relevant endoxifen concentration required to produce optimal tumor suppression. Based on the PK–PD model and simulations using clinical PK/concentration data of endoxifen, C stasis (100 % TGI) is observed at 53 nM, a concentration attained by many tamoxifen-treated patients. Importantly, PK–PD simulations indicate that mean steady-state levels observed in CYP2D6 extensive metabolizers are expected to result in optimal tumor suppression while mean concentrations observed in poor metabolizers are predicted to result in suboptimal TGI. Our study is the first to characterize the in vivo PK–PD relationship for endoxifen where clinically observed endoxifen concentrations are associated, in an exposure-dependent manner, with % TGI measured in a xenograft model. It is anticipated that endoxifen concentration achieved in individual patients is the limiting factor for achieving optimal tumor growth suppression.

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Acknowledgments

R.B.K. is supported by the Wolfe Medical Research Chair in Pharmacogenomics, Cancer Care Ontario Research Chair (Tier-1), and Ontario Institute of Cancer (OICR) Translational Research Team (TRT) grant. I.Y.G is supported by the Canadian Institutes of Health Research for the Doctoral Canada Graduate Scholarship. We would like to thank, Stephen Gould (Genentech Inc.), and Leanne Ross (Genentech Inc.) for contributing to the xenograft mouse model study design.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada

    Inna Y. Gong, Wendy A. Teft & Richard B. Kim

  2. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada

    Inna Y. Gong & Richard B. Kim

  3. Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS 412a, South San Francisco, CA, 94080, USA

    Justin Ly, Yung-Hsiang Chen, Bruno Alicke & Edna F. Choo

  4. Department of Medicine, LHSC-University Hospital, Room A-LL-152, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Richard B. Kim

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  1. Inna Y. Gong
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  2. Wendy A. Teft
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  4. Yung-Hsiang Chen
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  7. Edna F. Choo
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Correspondence to Richard B. Kim or Edna F. Choo.

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Gong, I.Y., Teft, W.A., Ly, J. et al. Determination of clinically therapeutic endoxifen concentrations based on efficacy from human MCF7 breast cancer xenografts. Breast Cancer Res Treat 139, 61–69 (2013). https://doi.org/10.1007/s10549-013-2530-1

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  • DOI: https://doi.org/10.1007/s10549-013-2530-1

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