This study uses data from the FAERS database and is currently the most comprehensive pharmacovigilance investigation on tivozanib after its launch. This research offers a precise and comprehensive portrayal of AEs linked to Tivozanib. Real-world monitoring of medication use and associated AEs after market release is crucial for confirming safety and efficacy. By analyzing FAERS data from Q2 2021 to Q4 2023, this study not only corroborated existing safety information but also uncovered potential new risks, providing valuable insights for clinical practice and public health policy. An in-depth analysis follows.
The disparity in Tivozanib-associated adverse events (AEs) between genders was evident, yet the substantial lack of gender data (97.99%) hindered a precise analysis of gender-specific reactions. Future efforts should prioritize the collection of gender-specific data to enhance our understanding of Tivozanib's adverse effects. The scarcity of age-related information also limited insights into AEs across different age groups, underscoring the need for more detailed age data in future research to examine age-related drug responses. The low rate of physician-reported cases (6.65%) points to a gap in physician engagement with adverse event reporting; increasing physician awareness and reporting is crucial. With the majority of reports (97.99%) originating from the United States, further research is necessary to explore potential regional or cultural influences on these findings.
A phase III trial8, highlighted common Tivozanib AEs, including hypertension and fatigue, alongside clinical abnormalities like proteinuria and elevated lipase. These findings match our FAERS database analysis, which didn't reveal new, intense AE signals for Tivozanib, echoing previously documented clinical trial and label data. This study, leveraging real-world evidence, offers a comprehensive view of Tivozanib's AE spectrum, affirming the consistency of observed AEs with prior clinical research.
Hypertension, previously proposed as a biomarker for Tivozanib efficacy 11., showed a dose-dependent increase in frequency across studies, affecting patients across varying dosage groups 12. In our study, hypertension-related AEs were among the top three, with 123 cases reported, underscoring the need for caution regarding hypertension when prescribing Tivozanib, especially in patients with pre-existing hypertension.
Hypothyroidism during TKI therapy, including Tivozanib, has been suggested as a response and efficacy biomarker 13. Our study noted a significant occurrence of hypothyroidism, indicating its potential as a key adverse reaction. The exact mechanism behind TKI-induced hypothyroidism remains unclear, although it's believed that VEGF/R-TKIs may inhibit thyroid hormone synthesis by acting as non-competitive inhibitors of thyroid peroxidase 14. Kappers et al. found that sunitinib significantly reduced thyroid capillaries in rats, supporting the capillary regression hypothesis for TKI-induced hypothyroidism 15. Additionally, TKIs may directly damage the thyroid gland, as indicated by increased TSH levels in patients, even with thyroid hormone replacement 16. Despite these insights, the precise mechanism and impact of hypothyroidism on cancer survival require further investigation 17.
Fatigue, with 264 reported cases, emerged as the most prevalent adverse reaction in our study. The pathophysiology of TKI-induced fatigue is complex and not fully understood, potentially involving VEGF suppression leading to conditions like hypothyroidism and hypophosphatemia, which contribute to muscle weakness and fatigue 18–22. Distinguishing between fatigue caused by cancer and that induced by treatment is challenging, as cancer-related fatigue may improve with therapy, while drug-related fatigue often worsens with increasing doses 23,24. Fatigue significantly affects cancer patients' quality of life and may impact survival25.
Considering fatigue's role as a dose-limiting toxicity in TKI treatment, proactive screening and early management are crucial 26. Our analysis, supported by prior research, highlights fatigue as a critical TKI side effect, underscoring the need for vigilance in monitoring and managing fatigue to enhance cancer patients' quality of life during Tivozanib therapy.
The described adverse events (AEs) and their potential mechanisms with Tivozanib remain speculative. Confirming the exact causes requires further investigation, considering the influence of drug properties, individual variability, and pre-existing conditions on AE development. Thus, additional clinical and experimental research is essential for a comprehensive understanding of AEs. Meanwhile, clinicians should closely monitor AE occurrence to manage them effectively.
Despite its insights into Tivozanib's safety, the study has drawbacks, mainly due to the voluntary nature of FAERS reports that might not accurately reflect all adverse events (AEs) due to factors like FDA alerts. Furthermore, the statistical methods used highlight potential safety signals without confirming actual risks, as the FAERS database doesn't verify the causality of drug-related AEs, often lacking in detailed patient information. This necessitates further research to validate findings and understand AEs better. Nonetheless, it underscores the importance of vigilant monitoring of AEs in clinical settings to guide Tivozanib's safe use.