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Minimal PK/PD model for simultaneous description of the maximal tolerated dose and metronomic treatment outcomes in mouse tumor models

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Abstract

Purpose

Metronomic chemotherapy (MC) is a promising approach where, in contrast to the conventional maximal tolerated dose (MTD) strategy, regular fractionated doses of the drug are used. This approach has proven its efficacy, although drug dosing and scheduling are often chosen empirically. Pharmacokinetic/pharmacodynamic (PK/PD) models provide a way to choose optimal protocols with computational methods. Existing models are usually too complicated and are valid for only a subset of drug schedules. To address this issue, we propose herein a simple model that can describe MC and MTD regimens simultaneously.

Methods

The minimal model comprises tumor suppression due to antiangiogenic drug effect together with a cell-kill term, responsible for its cytotoxicity. The model was tested on data obtained on tumor-bearing mice treated with gemcitabine in ether MTD, MC, or combined (MTD + MC) regimens.

Results

We conducted a number of tests in which data were divided in various ways into training and validation sets. The model successfully described different trends in the MTD and MC regimens. With parameters obtained by fitting the model to MTD data, the simulations correctly predicted trends in both the MC and combined therapy groups.

Conclusion

Our results demonstrate that the proposed model presents a minimal yet efficient tool for modeling outcomes in different treatment regimens in mice. We hope that this model has the potential for use in clinical practice in the development of patient-specific chemotherapy scheduling protocols based on observed treatment response.

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Data availability

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Saint-Petersburg Clinical Scientific and Practical Center of Specialized Types of Medical Care (Oncological), St. Petersburg, Russia

    Ivan N. Terterov, Vyacheslav A. Chubenko, Nikolay A. Knyazev, Vladimir V. Klimenko, Andrei A. Bogdanov, Vladimir M. Moiseyenko & Alexey A. Bogdanov

Authors
  1. Ivan N. Terterov
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  2. Vyacheslav A. Chubenko
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  3. Nikolay A. Knyazev
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  4. Vladimir V. Klimenko
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  5. Andrei A. Bogdanov
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  6. Vladimir M. Moiseyenko
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  7. Alexey A. Bogdanov
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Correspondence to Ivan N. Terterov.

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Terterov, I.N., Chubenko, V.A., Knyazev, N.A. et al. Minimal PK/PD model for simultaneous description of the maximal tolerated dose and metronomic treatment outcomes in mouse tumor models. Cancer Chemother Pharmacol 88, 867–878 (2021). https://doi.org/10.1007/s00280-021-04326-x

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  • DOI: https://doi.org/10.1007/s00280-021-04326-x

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