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Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra

Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
ERJ Open Research 2022; DOI: 10.1183/23120541.00245-2022
Koji Kuronuma
1Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
4These authors contributed equally to first authorship
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  • For correspondence: kuronumak@sapmed.ac.jp
Natsumi Susai
2Biomarker R&D Department, Shionogi & Co., Ltd., Toyonaka, Japan
4These authors contributed equally to first authorship
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Tomohiro Kuroita
2Biomarker R&D Department, Shionogi & Co., Ltd., Toyonaka, Japan
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto , Japan
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Hiroki Yamamoto
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto , Japan
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Takeshi Yoshioka
2Biomarker R&D Department, Shionogi & Co., Ltd., Toyonaka, Japan
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Shuji Kaneko
3Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto , Japan
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Hirofumi Chiba
1Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Abstract

Background Pirfenidone (PFD) is widely used in patients with idiopathic pulmonary fibrosis (IPF), and its adverse effects, such as nausea and photosensitivity, are well known. Many patients with IPF have reduced doses or even cessation of PFD because of its side effects. No solutions have been found for these side effects because the current mechanistic insights are insufficient.

Methods Using the results of real-world data analysis from the Food and Drug Administration Adverse Events Reporting System, we hypothesised that PFD-related symptoms may be similar to pellagra. Reverse translational experiments using female Balb/c mice were performed to validate and estimate this hypothesis. Niacin and its metabolite responses were compared between patients with IPF treated by PFD and those treated without PFD.

Results The pellagra hypothesis was translated from real-world data analysis. Pharmacological and comprehensive genetic investigations showed that PFD caused pellagra-related nausea and photosensitivity in a mouse model, which may have been mediated by the actions of nicotinamide N-methyltransferase. Higher nicotinamide N-methyltransferase substrate responses were observed in urine from patients and mice with PFD than in those without PFD.

Conclusions PFD may cause pellagra or pellagra-like symptoms such as photosensitivity. Further studies are required to investigate whether niacin prevents pellagra-like symptoms caused by PFD in patients with IPF.

Footnotes

This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.

Conflict of interest: Tomohiro Kuroita, Natsumi Susai, and Takeshi Yoshioka are employees of Shionogi & Co., Ltd. Other authors declare no competing interests.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received May 18, 2022.
  • Accepted July 20, 2022.
  • Copyright ©The authors 2022
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra
Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
ERJ Open Research Jan 2022, 00245-2022; DOI: 10.1183/23120541.00245-2022

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Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra
Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Hiroki Yamamoto, Takeshi Yoshioka, Shuji Kaneko, Hirofumi Chiba
ERJ Open Research Jan 2022, 00245-2022; DOI: 10.1183/23120541.00245-2022
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