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Relationship between Anaplastic Lymphoma Kinase Inhibitors and Epileptic Seizure Disorder: A Post-Marketing

Yoshihiro Noguchi^1,2, Hiroki Asano³, Rikuto Masuda¹

¹Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan.

|May 20, 2024

Abstract

Introduction:

Anaplastic lymphoma kinase (ALK) has been to be involved in the uptake and regulation of dopamine 2 receptor (D2R), a G protein-coupled receptor expressed in various brain regions. Therefore, it is crucial to understand the relationship between ALK inhibitors and seizures is an important issue. This study investigated the relationship between ALK inhibitors and seizures.

Methods:

This study investigated the relationship between ALK inhibitors and seizures through a disproportionality analysis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The target drugs were the ALK inhibitors crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The seizures covered were defined high-level group term (HLGT): "Seizures (incl. subtype)" including high-level term (HLT): "seizures and seizure disorders NEC." This study used the information component (IC), a signal score, as a Bayesian statistical method for disproportionality analysis. The signal detection criteria used in this study were the same as those reported previously: a lower limit of 95% credible interval (CrI) for IC >0.

Results:

The signal scores of '"seizures and seizure disorders not elsewhere classified (NEC)" "for each ALK inhibitor were crizotinib (IC: -0.00052, 95% CrI: -0.38-0.27), ceritinib (IC: 1.18, 95% CrI: 0.68-1.54), alectinib (IC: 0.68, 95% CrI: 0.19-1.02), brigatinib (IC: 1.04, 95% CrI: 0.32-1.54), and lorlatinib (IC: 0.82, 95% CrI: 0.11-1.32). On the other hand, "generalized tonic-clonic seizures," "partial simple seizures NEC," "absence seizures," and "partial complex seizures" had no or few reported cases, and no signal was detected.

Conclusion:

To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures.

Insights

This study found that certain anaplastic lymphoma kinase (ALK) inhibitors, specifically ceritinib, alectinib, brigatinib, and lorlatinib, are associated with an increased risk of seizures. These findings highlight potential neurological side effects of these targeted cancer therapies.

Area of Science:

Oncology
Pharmacovigilance
Neuroscience

Background:

Anaplastic lymphoma kinase (ALK) plays a role in dopamine 2 receptor (D2R) regulation.
Understanding the link between ALK inhibitors and seizures is critical due to potential central nervous system effects.

Purpose of the Study:

To investigate the association between ALK inhibitors and seizure risk.
To analyze post-marketing surveillance data for adverse events related to ALK inhibitors and seizures.

Main Methods:

Disproportionality analysis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).
Included ALK inhibitors: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib.
Analyzed "seizures and seizure disorders NEC" using the information component (IC) Bayesian statistical method.

Main Results:

A significant association between seizures and ceritinib (IC: 1.18), alectinib (IC: 0.68), brigatinib (IC: 1.04), and lorlatinib (IC: 0.82) was detected.
Crizotinib showed no significant association with seizures (IC: -0.00052).
No signals were detected for specific seizure types like generalized tonic-clonic or absence seizures.

Conclusions:

This is the first study to evaluate ALK inhibitors and seizures using post-marketing data.
Ceritinib, alectinib, brigatinib, and lorlatinib, which exhibit high brain penetration, are associated with an increased risk of seizures.
Clinical vigilance for seizure events is recommended when prescribing these ALK inhibitors.

Read full analysis

Keywords:

Anaplastic lymphoma kinase inhibitors Disproportionality analysis Epileptic seizure disorder FDA Adverse Event Reporting System

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