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The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers

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Abstract

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35%–47% reduction in metabolic clearance attributed to UGT1A1/2B7 glucuronidation, CYP2A6/3A4/2C9 metabolism, and β-oxidation. These hepatic impairment effects reduced between-subject variability by only 5%–8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population.

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Data availability

The datasets used for this analysis are available upon reasonable request from the corresponding author after permission of the sponsor.

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Acknowledgements

This study was supported by the following grants: UM1 CA186690, U24CA247643, R50CA211241, and P30CA47904 (NCI).

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Author notes

  1. Shivaani Kummar

    Present address: Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

  2. Jan H. Beumer and Jogarao V. S. Gobburu equally contributed to this work.

Authors and Affiliations

  1. Center for Translational Medicine, University of Maryland, Baltimore, MD, USA

    Allison Dunn & Jogarao V. S. Gobburu

  2. Early Clinical Trials Development Program, National Cancer Institute, Bethesda, USA

    Naoko Takebe, Alice Chen & Nancy Moore

  3. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA

    Shivaani Kummar & James Doroshow

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA

    Richard Piekarz

  5. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Brian Kiesel & Jan H. Beumer

  6. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan H. Beumer

  7. Division of Hematology‐Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jan H. Beumer

  8. Department of Practice, Sciences and Health Outcomes Research, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD, 21201, USA

    Allison Dunn

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  1. Allison Dunn
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Contributions

A.D. performed the analysis and wrote the main manuscript text. All authors reviewed the manuscript and provided valuable domain expertise that influenced the research conducted.

Corresponding author

Correspondence to Allison Dunn.

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Conflict OF Interest

J.G. is a co-founder of Pumas AI, the company that developed the software, Pumas, which was used to develop the population PK model.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The data was generated in trials registered under ClinicalTrials.gov Identifier NCT01273155.

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Dunn, A., Takebe, N., Chen, A. et al. The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04651-x

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