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

Takahiro Niimura (), Koji Miyata, Hirofumi Hamano, Yuuki Nounin, Hiroto Unten, Masaki Yoshino, Satoru Mitsuboshi, Fuka Aizawa, Kenta Yagi, Toshihiro Koyama, Mitsuhiro Goda, Yasunari Kanda, Yuki Izawa-Ishizawa, Yoshito Zamami and Keisuke Ishizawa
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Takahiro Niimura: Tokushima University Graduate School of Biomedical Sciences
Koji Miyata: Tokushima University Graduate School of Biomedical Sciences
Hirofumi Hamano: Tokushima University Hospital
Yuuki Nounin: Tokushima University Graduate School of Biomedical Sciences
Hiroto Unten: Tokushima University Graduate School of Biomedical Sciences
Masaki Yoshino: Niigata Prefectural Cancer Center Hospital
Satoru Mitsuboshi: Kaetsu Hospital
Fuka Aizawa: Tokushima University Graduate School of Biomedical Sciences
Kenta Yagi: Tokushima University Graduate School of Biomedical Sciences
Toshihiro Koyama: Okayama University
Mitsuhiro Goda: Tokushima University Graduate School of Biomedical Sciences
Yasunari Kanda: National Institute of Health Sciences
Yuki Izawa-Ishizawa: Tokushima University Graduate School of Biomedical Sciences
Yoshito Zamami: Tokushima University Graduate School of Biomedical Sciences
Keisuke Ishizawa: Tokushima University Graduate School of Biomedical Sciences

Drug Safety, 2023, vol. 46, issue 6, No 3, 545-552

Abstract: 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.

Date: 2023
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DOI: 10.1007/s40264-023-01300-9

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