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Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase)

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Abstract

Introduction

Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear.

Aims

This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database.

Methods

We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed.

Results

Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63–6.15], ceritinib [ROR, 12.9; 95% CI 9.37–17.79], alectinib [ROR, 4.8; 95% CI 3.15–7.42], brigatinib [ROR, 3.5; 95% CI 1.33–9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60–11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72–6.77) and ceritinib (ROR, 4.2; 95% CI 2.17–8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88–5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60–2.90), crizotinib (ROR, 2.1; 95% CI 1.72–2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27–3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib.

Conclusions

Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

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Acknowledgments

The study results and conclusions do not represent the opinion of the Uppsala Monitoring Centre, National Centers, or WHO.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

    Takahiro Niimura, Koji Miyata, Yuuki Nounin, Hiroto Unten, Fuka Aizawa, Kenta Yagi, Mitsuhiro Goda, Yuki Izawa-Ishizawa, Yoshito Zamami & Keisuke Ishizawa

  2. Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan

    Takahiro Niimura, Hirofumi Hamano, Kenta Yagi & Keisuke Ishizawa

  3. Department of Pharmacy, Okayama University Hospital, Okayama, Japan

    Hirofumi Hamano & Yoshito Zamami

  4. Department of Pharmacy, Niigata Prefectural Cancer Center Hospital, Niigata, Japan

    Masaki Yoshino

  5. Department of Pharmacy, Kaetsu Hospital, Niigata, Japan

    Satoru Mitsuboshi

  6. Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan

    Hiroto Unten, Fuka Aizawa, Mitsuhiro Goda & Keisuke Ishizawa

  7. Department of Health Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Toshihiro Koyama

  8. Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Japan

    Yasunari Kanda

  9. Department of General Medicine, Taoka Hospital, Tokushima, Japan

    Yuki Izawa-Ishizawa

Authors
  1. Takahiro Niimura
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Corresponding author

Correspondence to Takahiro Niimura.

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Funding

This research was supported by grants from the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research [Grant number: 21K20720, 22K15319] and Grant-in-Aid for Transformative Research Areas (B) [Grant number: 20H05798].

Conflicts of interest

The authors declare no potential conflicts of interest.

Ethics approval

Not applicable.

Consent to Participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

The data that support the findings of this study are available from VigiBase, were used under license, and are, therefore, not publicly available. Data are available from VigiBase with the permission of Uppsala Monitoring Centre.

Code availability

The code used when analyzing the data of the current study is available from the corresponding author on reasonable request.

Author contributions

TN authored the article and performed the statistical analysis. HH conceptualized the study and was involved in planning and interpretation of results. KM, YN, HU, MY, SM, FA, KY, TK, MG, YK, YI, YZ, and KI critically revised the manuscript and interpreted the results. All authors read and approved the final version.

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Niimura, T., Miyata, K., Hamano, H. et al. Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase). Drug Saf 46, 545–552 (2023). https://doi.org/10.1007/s40264-023-01300-9

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  • DOI: https://doi.org/10.1007/s40264-023-01300-9

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