Hypophosphatemia as a Potential Class Effect of Histone Deacetylase Inhibitors: Evidence from Disproportionality Analysis and Mendelian Randomization Analysis of Drug Targets

Background/Objective: Histone deacetylase inhibitors (HDACi) represent a novel class of antineoplastic agents, yet their comprehensive safety profile warrants further investigation. This study aimed to examine the safety of HDACi using the FDA Adverse Event Reporting System (FAERS) and to explore causal relationships through Mendelian randomization (MR) analysis of drug targets. Methods: Adverse drug event (ADE) reports for Vorinostat, Romidepsin, Belinostat, and Panobinostat submitted to the FAERS from their respective market entry dates through 31 December 2023, were analyzed using disproportionality analyses with four algorithms, supplemented by time-to-onset analysis, logistic regression, and MR analysis. Results: A total of 1360, 1065, 225, and 1234 ADE reports were documented for Vorinostat, Romidepsin, Belinostat, and Panobinostat, respectively. Eight preferred terms, including decreased white blood cell, platelet, and neutrophil counts, hypophosphatemia, hypocalcemia, QT prolongation, increased aspartate aminotransferase, and anemia, exhibited positive signals across all four HDACi. A temporal decline in the risk of most HDACi-related ADEs was observed, and age, gender, and weight were identified as potential confounding factors for important medical events. Notably, MR analysis revealed a positive correlation between HDAC5 expression and serum phosphate levels. Conclusions: This pharmacovigilance study provides hypothesis-generating evidence that hypophosphatemia may represent a potential class effect of HDACi.