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Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice

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Abstract

Trastuzumab-DM1 (T-DM1) is a novel antibody–drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time–dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.

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Authors and Affiliations

  1. Department of Pharmacokinetics, Pharmacodynamics, and Bioanalytical Sciences, Genentech, Inc., 1 DNA Way, MS463, South San Francisco, CA, 94080, USA

    Nelson L. Jumbe, Yan Xin, Douglas D. Leipold, Paul J. Fielder & Jay Tibbitts

  2. Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA

    Lisa Crocker, Debra Dugger & Mark X. Sliwkowski

  3. Assay Automation and Technology, Genentech, Inc., South San Francisco, CA, USA

    Elaine Mai

Authors
  1. Nelson L. Jumbe
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  2. Yan Xin
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  3. Douglas D. Leipold
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  4. Lisa Crocker
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  5. Debra Dugger
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  6. Elaine Mai
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  7. Mark X. Sliwkowski
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  8. Paul J. Fielder
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  9. Jay Tibbitts
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Corresponding author

Correspondence to Jay Tibbitts.

Additional information

In this study, pharmacokinetic/pharmacodynamic modeling successfully integrated the exposure–anti-tumor activity relationships providing insight on a predicted efficacious clinical dose and dosing regimen for T-DM1.

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Jumbe, N.L., Xin, Y., Leipold, D.D. et al. Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice. J Pharmacokinet Pharmacodyn 37, 221–242 (2010). https://doi.org/10.1007/s10928-010-9156-2

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  • DOI: https://doi.org/10.1007/s10928-010-9156-2

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