Cardiotoxicity of different 5-HT3 receptor antagonists analyzed using the FAERS database and pharmacokinetic study

To comprehensively compare the risk of cardiotoxicity with 5-HT3 receptor antagonists (5-HT3RAs) and to explore the underlying pharmacokinetic factors that might contribute to cardiotoxicity. The FDA Adverse Event Reporting System (FAERS) data (January 2004 to March 2023) were extracted. Disproportionality analysis, sensitivity analyses, and time-to-onset assessments were conducted to evaluate cardiac risk signals associated with 5-HT3RAs. Physiologically based pharmacokinetic (PBPK) models were developed to study the drug distribution characteristics in cardiac tissues. After excluding duplicate reports, a total of 1174 reports of cardiotoxicity related to 5-HT3RAs (including ondansetron, granisetron and palonosetron) were identified in the FAERS database. Removing cases with diagnosed heart disease and electrolyte disorders at baseline, all cardiotoxicity signals persisted except the arrhythmia signal in palonosetron. Stratified sensitivity analyses (pre-/post-2012 FDA safety alert) revealed the signal for electrocardiogram QT prolonged persisted both in pre-alert and post-alert. Palonosetron demonstrated a longer latency than ondansetron and granisetron, which exhibited similar time-to-onset 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. The study revealed that different 5-HT3RAs exhibited varying degrees and types of cardiotoxicity. Among these, ondansetron demonstrated the highest signals of cardiotoxicity, followed by palonosetron, with granisetron showing the least. Ondansetron concentration in cardiac tissue far exceeded that in plasma, which might partially explain the observed cardiotoxicity. In conclusion, it suggested to prioritize low cardiac toxicity 5-HT3RAs for patients especially for those with heart diseases, and to strengthen the monitoring and management of cardiac toxicity furtherly.