Cardiotoxicity associated with different 5-HT3RAs: pharmacovigilance analysis of the FDA Adverse Event Reporting System database study and a pharmacokinetic study

Purpose To comprehensively compare the risk of cardiotoxicity with 5-HT3RAs and to explore the underlying pharmacokinetic factors that might partially contribute to cardiotoxicity. Methods The FDA Adverse Event Reporting System (FAERS) data (January 2004 to March 2023) were extracted. Disproportionality analysis by calculating the relative odds ratio (ROR) and sensitivity analyses were conducted to assess cardiac risk signals of 5-HT3RAs. Additionally, various parameter distributions were tested for time-to-onset analysis to describe the latency of cardiac AEs induced by 5-HT3RAs. Physiologically based pharmacokinetic (PBPK) models were developed to study the drug distribution characteristics in cardiac tissues. Results A total of 1,174 reports of cardiotoxicity related to 5-HT3RAs (including ondansetron, granisetron and palonosetron) were identified in the FAERS database. Ondansetron had an electrocardiogram QT prolonged ROR ₀₂₅ of 11.21, while that of granisetron and palonosetron were 1.07 and 3.42, respectively. Removing cases with diagnosed heart disease and electrolyte disorders at baseline, all cardiotoxicity signals persisted except the arrhythmia signal in palonosetron. The median onset time of cardiac AEs associated with 5-HT3RAs was 0.5 days (interquartile ranges (IQR): 0.5–7.5 days). Notably, palonosetron demonstrated a longer latency than ondansetron and granisetron, which exhibited similar time-to-onset (TTO) values. The PBPK model extrapolation results showed that ondansetron concentration in cardiac tissue was 2.3 times higher than that in plasma, which might support that it is more susceptible to cardiotoxicity. Conclusion It suggested prioritizing low cardiac toxicity 5-HT3RAs for patients especially for those with heart diseases, and strengthening the monitoring and management of cardiac toxicity further.