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Predicting Chemotherapy-Induced Neutropenia and Granulocyte Colony–Stimulating Factor Response Using Model-Based In Vitro to Clinical Translation

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Abstract

The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug’s mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model’s drug effect parameters. Population simulations were performed to predict the absolute neutrophil count (ANC) and incidence of neutropenia for each compound, which were compared to results reported in the literature. In addition, using the single agent in vitro study results, the model was able to predict ANC time course in response to paclitaxel plus carboplatin in combination, which compared favorably to the results reported in a phase 1 clinical trial of 46 patients (r2 = 0.70). Model simulations were used to compare the relative risk (RR) of neutropenia in patients with high baseline ANCs for five chemotherapeutic regimens: doxorubicin (RR = 0.59), paclitaxel plus carboplatin combination (RR = 0.079), carboplatin (RR = 0.047), paclitaxel (RR = 0.031), and gemcitabine (RR = 0.013). Finally, the model was applied to quantify the reduced incidence of neutropenia with coadministration of pegfilgrastim or filgrastim, for both paclitaxel and the combination of paclitaxel plus carboplatin. The model provides a framework for predicting clinical neutropenia using in vitro bone marrow studies of anticancer agents that may guide drug development decisions.

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Acknowledgments

We gratefully acknowledge Dr. Jan H. Beumer of the Cancer Therapeutics Program, and the Departments of Pharmaceutical Sciences and Medicine at the University of Pittsburgh for providing the paclitaxel/carboplatin clinical trial data. The work was presented originally at the American Conference on Pharmacometrics in 2019, Orlando, FL.

Funding

This work was supported by grants from National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) P41-EB001978 and the Alfred E. Mann Institute at USC (DZD).

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Southern California, Los Angeles, California, 90089, USA

    Wenbo Chen & David Z. D’Argenio

  2. Pfizer Worldwide Research, Development and Medicine, San Diego, California, USA

    Britton Boras, Tae Sung, Wenyue Hu & Mary E. Spilker

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  1. Wenbo Chen
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Correspondence to David Z. D’Argenio.

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W. Chen and D.Z. D’Argenio declare no conflict of interests. B. Boras, T. Sung, W. Hu, and M.E. Spilker are employees of Pfizer, Inc. These authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Chen, W., Boras, B., Sung, T. et al. Predicting Chemotherapy-Induced Neutropenia and Granulocyte Colony–Stimulating Factor Response Using Model-Based In Vitro to Clinical Translation. AAPS J 22, 143 (2020). https://doi.org/10.1208/s12248-020-00529-x

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