Zhuda Meng,1,* Liying Song,2,* Shuang Wang,3,* Guosheng Duan4 

1Department of Thyroid Surgery, Changzhi People’s Hospital, Changzhi, People’s Republic of China; 2Department of Thyroid Surgery, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Gastroenterology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China; 4Radiotherapy Department, Shanxi Provincial Peoples Hospital: Fifth Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Zhuda Meng, Department of Thyroid Surgery, Changzhi People’s Hospital, Changzhi, 046000, People’s Republic of China, Email jzx23456m@163.com

Purpose: This study aims to investigate the potential association between non-selective RET kinase inhibitors and thyroid dysfunction (TD) by conducting a pharmacovigilance analysis using data from the US FDA Adverse Event Reporting System (FAERS).
Methods: Data for non-selective RET MKIs were obtained from the FAERS database, spanning the first quarter of 2015 to the fourth quarter of 2023. Disproportionality analysis was used to quantify the AE signals associated with non-selective RET MKIs and to identify TD AEs. Subgroup analyses and multivariate logistic regressions were used to assess the factors influencing the occurrence of TD AEs. Time-to-onset (TTO) analysis and the Weibull Shape Parameter (WSP) test were also performed.
Results: Descriptive analysis revealed an increasing trend in TD adverse events linked to non-selective RET MKIs, with a notable proportion of serious reactions reported. Disproportionality analysis using ROR, PRR, BCPNN, and EBGM algorithms consistently demonstrated a positive association between Sunitinib, Cabozantinib, and Lenvatinib with TD adverse events. Subgroup analyses highlighted differential susceptibility to TD based on age, gender, and weight, with varying patterns observed for each inhibitor. Logistic regression analyses identified factors independently influencing the occurrence of TD adverse events, emphasizing the importance of age, gender, and weight in patient stratification. Time-to-onset analysis indicated early manifestation of TD adverse events following treatment with non-selective RET MKIs, with a decreasing risk over time.
Conclusion: The results of our study indicate a correlation between the use of non-selective RET MKIs and the occurrence of TD AEs. This may provide support for the clinical monitoring and risk identification of non-selective RET MKIs. Nevertheless, further clinical studies are required to substantiate the findings of this study.

Keywords: drug-induced thyroid dysfunction, non-selective RET MKIs, pharmacovigilance, FDA adverse event reporting system, clinical monitoring