Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor-Associated Cardiotoxicity: A Recent Five-Year Pharmacovigilance Study

Abstract

Background: Clinical trials frequently reported anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) associated with cardiac adverse drug events (AEs) but minimal postmarketing data. We aimed to research real-world cardiac disorders associated with ALK-TKIs based on the Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Extract reports from the FAERS from the first quarter of 2016 to the second quarter of 2021 were obtained. Data mining of cardiac disorders associated with ALK-TKIs was carried out using disproportionality analysis to determine the clinical characteristics of AEs.Results: In total, 605 cases were screened out. These events were found to be more prevalent in patients ≥45 years (50.74%) and women (50.74%). The onset time of cardiac disorders was variable and concentrated within 2 months, with a median time of 33 days. The outcomes tended to be poor, with 20.93% fatality proportion. Cardiac arrhythmia was a common adverse event of ALK-TKIs, especially bradycardia. Crizotinib and lorlatinib showed positive signals in cardiac disorders, especially in heart failure, and brigatinib presented no signals. The study also found that myocarditis caused by ceritinib and cardiomyopathy caused by lorlatinib may be potential new adverse drug reactions.Conclusion: ALK-TKIs were reported more frequently in cardiotoxicity than other drugs and could often manifest earlier. We also found potential new AE signals in specific drugs and need more clinical studies to confirm. Our study helps fill the safety information of ALK-TKIs in the heart and provides directions for further research.

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database

“…Focusing on gender and age groups, females and the age group >65 years were the most reported as shown in a recent study ( 29 ). Moreover, the TTO was similar to those reported in other studies where EGFRi had a median TTO of 28 days especially for gastrointestinal and skin disorders ( 30 ), ALKi had a median TTO from 14 to 85 days depending on the type of ADR ( 31 , 32 ), while NTB had a median TTO of 13.5 days for liver injury ( 33 ).…”

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System

“…Despite its strengths, the SRS database has some intrinsic limitations, such as the underreporting phenomena, the absence of denominators (i.e., the total number of GIST patients who have undergone treatment with TKIs), and the poor quality of information listed in each ICSR (i.e., seriousness and outcome, previous/current medical conditions, additional suspected or concomitant drugs) that could potentially affect the occurrence of analyzed ADRs [ 65 ]. In contrast to other SRS database studies, the use of the EV database does not allow the detection of all ICSR information, making it impossible to compute disproportionality analyses for all ICSRs related to SOC Nervous system disorders and Psychiatric disorders [ 42 , 66 , 67 ]. Therefore, further ad hoc studies are essential to establish the real neuropsychiatric safety profile of TKIs used in GISTs.…”

Virtual drug screen reveals context-dependent inhibition of cardiomyocyte hypertrophy

“…Irbesartan is an angiotensin receptor blocker (ARB) used for hypertension and known to inhibit hypertrophy 70 . Brigatinib shows minimal cardiotoxicity compared to other ALK-tyrosine kinase inhibitors 71 , but has not been tested in the context of hypertrophy. Although each drug alone is predicted to inhibit hypertrophy to some extent, the combination of both drugs predicts an improved outcome.…”