Sex-Specific Safety Profiles of PI3K Inhibitors: A Real-World Pharmacovigilance Study Based on FAERS Database

This study aimed to investigate the sex-associated adverse events (AEs) reporting differences of phosphatidylinositol 3-kinase (PI3K) inhibitors from the US Food and Drug Administration Adverse Event Reporting System (FAERS), thereby providing a more solid foundation for evidence-based clinical practice.

All PI3K inhibitors were searched as primary and secondary suspected drugs from FAERS data (January 2004 to July 2025). We performed disproportionality analyses using reporting odds ratios (ROR) to evaluate the associations between PI3K inhibitors and adverse events.

Among the 6,209 AE reports associated with PI3K inhibitors, alpelisib exhibited a female predominance (82.7%), accompanied by a stronger hyperglycaemia signal in females (reporting odds ratio [ROR] 187.6 vs 79.3). Following false discovery rate (FDR) correction, significant sex differences at the preferred term (PT) level persisted for alpelisib (female predominance in hyperglycaemia, rash, and diarrhoea), yet no significant differences at the system organ class (SOC) level remained. Idelalisib demonstrated a male predominance (54.9%), with comparable diarrhoea signals between the sexes. Regarding copanlisib and duvelisib, the limited number of cases precluded reliable sex-specific comparisons.

This research identifies sex-specific AE patterns for PI3K inhibitors. Subsequent to FDR correction, significant PT level sex differences were detected for alpelisib, yet not for idelalisib. Moreover, no differences at the standard of care SOC level persisted for either drug. The findings regarding copanlisib and duvelisib remain indeterminate. These results provide clinically relevant signals for sex-tailored AE surveillance and necessitate prospective validation.