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A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts

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Abstract

Purpose

The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of-action/toxicity of doxorubicin in humans.

Methods

The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans. The multiscale dispositions of doxorubicin in human heart and tumors were explicitly simulated to elucidate the potential mechanisms of its cytotoxicity and cardiotoxicity.

Results

The developed PBPK model was able to adequately describe doxorubicin dispositions in mice, rats and humans. In humans, prolonged infusion, a dosing regimen with less cardiotoxicity, was predicted with substantially reduced free doxorubicin concentrations at human heart interstitium, which were lower than the concentrations associated with oxidative stress. However, prolonged infusion did not reduce doxorubicin-DNA adduct at tumor nucleus, consistent with clinical observations that prolonged infusion did not compromise anti-tumor effect, indicating that one primary anti-tumor mechanism was DNA torsion.

Conclusions

A multiscale PBPK model for doxorubicin was developed and further applied to explore its cytotoxic and cardiotoxic mechanisms.

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ACKNOWLEDGMENTS and DISCLOSURES

This work was supported by FDA (U01 FD005206) and NIH (GM119661). The views expressed in this article are those of the authors and not necessarily those of the Food and Drug Administration (FDA). We appreciate the discussion and suggestions with Dr. William Jusko from State University of New York at Buffalo. There is no conflict of interest.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA

    Hua He, Can Liu & Yanguang Cao

  2. Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China

    Hua He

  3. Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA

    Yun Wu

  4. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Xinyuan Zhang & Jianghong Fan

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  1. Hua He
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  2. Can Liu
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Correspondence to Yanguang Cao.

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He, H., Liu, C., Wu, Y. et al. A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts. Pharm Res 35, 174 (2018). https://doi.org/10.1007/s11095-018-2456-8

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  • DOI: https://doi.org/10.1007/s11095-018-2456-8

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