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Pharmacokinetics of single-agent axitinib across multiple solid tumor types

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Abstract

Purpose

Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors.

Methods

The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration (C max) and area under the plasma concentration–time curve (AUC) of data from these tumor populations was compared to C max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types.

Results

Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1 L/h, 56.2 L, 1.26/h−1, 0.663, and 0.448 h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma.

Conclusion

The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.

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Acknowledgments

This study was sponsored by Pfizer Inc. Medical writing support was provided by Mariko Nagashima, PhD, at Engage Scientific Solutions (Southport, CT, USA) and was funded by Pfizer Inc.

Conflict of interest

The current study and trials included in the analyses were funded by Pfizer Inc. Yazdi K. Pithavala and Ana Ruiz-Garcia are employees of and own stock in Pfizer Inc. Michael A. Tortorici, May Garrett, and Sinil Kim were employed at Pfizer Inc during the time of this study and development of the manuscript. Michael A. Tortorici is currently an employee of CSL Behring Biotherapies for Life™ and owns stock in Pfizer Inc. May Garrett is currently a contracted employee of and owns stock in Pfizer Inc. Sinil Kim is currently an employee of Mirna Therapeutics and owns stock in Pfizer Inc and Mirna Therapeutics Inc. Ezra E.W. Cohen has nothing to disclose. John P. Fruehauf received research funding from Pfizer Inc.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA

    Michael A. Tortorici, Yazdi K. Pithavala & Ana Ruiz-Garcia

  2. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    Ezra E. W. Cohen

  3. Pfizer Global Pharmacometrics, Pfizer Inc, San Diego, CA, USA

    May Garrett

  4. Clinical Oncology, Pfizer Inc, San Diego, CA, USA

    Sinil Kim

  5. Department of Medicine, Pharmaceutical Sciences, Biological Chemistry, and Biomedical Engineering, University of California-Irvine, Orange, CA, USA

    John P. Fruehauf

  6. Clinical Pharmacology and Pharmacometrics, CSL Behring Biotherapies for Life™, 1020 First Avenue, King of Prussia, PA, 19406, USA

    Michael A. Tortorici

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  1. Michael A. Tortorici
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Correspondence to Michael A. Tortorici.

Additional information

Michael A. Tortorici, May Garrett, and Sinil Kim were employed at Pfizer Inc during the time of this study and development of the manuscript.

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Tortorici, M.A., Cohen, E.E.W., Pithavala, Y.K. et al. Pharmacokinetics of single-agent axitinib across multiple solid tumor types. Cancer Chemother Pharmacol 74, 1279–1289 (2014). https://doi.org/10.1007/s00280-014-2606-6

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  • DOI: https://doi.org/10.1007/s00280-014-2606-6

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