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The Occurrence of Encephalitis Due to Immune Checkpoint Inhibitors: A Pharmacovigilance Study

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Abstract

Purpose

Immune checkpoint inhibitors (ICIs) are associated with peculiar adverse events related to the mechanism of action. Less than 1% of patients treated with ICIs develop autoimmune encephalitis. The aim of this study was to compare the frequency of encephalitis development due to ICIs with encephalitis due to other drugs using the Japanese Adverse Drug Event Report (JADER) database and Bayesian confidence propagation neural networks for signal detection.

Methods

Data from the JADER database from April 2004 to December 2020 were downloaded via the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Information Component (IC) values were calculated as an index of signal detection based on the Bayesian method.

Results

The lower bound of the 95% credible interval (CI) of the IC values for atezolizumab and pembrolizumab were greater than 0 in most of the periods. Thus, encephalitis occurred more frequently for atezolizumab and pembrolizumab than for other drugs. For nivolumab and ipilimumab, a significant signal was detected only for recent data. In contrast, the lower bounds of the 95% CIs for avelumab and durvalumab were smaller than 0 in most of the periods because encephalitis was seldom reported for avelumab and durvalumab.

Conclusions

We showed that encephalitis occurs more frequently for atezolizumab, pembrolizumab, nivolumab, and ipilimumab compared with the frequency for other drugs. The time of onset varied widely, and patients should be monitored for more than 1 year after the last administration of ICIs.

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Availability of Data and Material

The pharmacovigilance data for this study are available in the Japanese Adverse Drug Event Report database from the Pharmaceuticals and Medical Devices Agency website at https://www.pmda.go.jp/. The Preferred Terms used in this study are available from the Medical Dictionary for Regulatory Activities/Japanese (MedDRA) Version 23.1. Restrictions apply to the availability of these data, which were used under license for this study. Data are available at https://www.pmrj.jp/jmo/php/indexe.php with the permission of MedDRA.

Code Availability

Not applicable.

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Acknowledgements

I certify that no individuals other than the listed co-authors contributed to this publication.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Yugo Chisaki, Hiroki Hata, Chikako Matsumura & Yoshitaka Yano

  2. Department of Pharmacy, National Hospital Organization Osaka National Hospital, 2-1-14-Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan

    Hiroki Hata

Authors
  1. Yugo Chisaki
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  2. Hiroki Hata
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  3. Chikako Matsumura
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  4. Yoshitaka Yano
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Contributions

YC: conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing—original draft, visualization, project administration, and funding acquisition. HH: investigation. CM: writing—review. YY: writing—review & editing, supervision.

Corresponding author

Correspondence to Yoshitaka Yano.

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Chisaki, Y., Hata, H., Matsumura, C. et al. The Occurrence of Encephalitis Due to Immune Checkpoint Inhibitors: A Pharmacovigilance Study. Ther Innov Regul Sci 56, 323–332 (2022). https://doi.org/10.1007/s43441-021-00365-x

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  • DOI: https://doi.org/10.1007/s43441-021-00365-x

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