Elucidating adverse drug reactions and underlying molecular mechanisms of ivermectin through pharmacovigilance and multi-omics analysis

Abstract

Objective The comprehensive safety profile and underlying molecular mechanisms of ivermectin-associated adverse drug reactions (ADRs) remain to be fully elucidated. Methods We integrated pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) with network toxicology and transcriptomic validation. Disproportionality analyses were conducted on 1,421 ivermectin-related reports to detect signals at the System Organ Class (SOC) and Preferred Term (PT) levels. Network-based approaches, including protein-protein interaction (PPI) analysis and molecular docking, were employed to identify core toxicity targets, followed by ADMET property prediction. Results Significant safety signals emerged for Eye disorders, Nervous system disorders, and General disorders. Frequently reported PTs included asthenia, headache, and pyrexia, alongside notable serious signals such as encephalopathy (ROR = 24.1) and toxic encephalopathy (ROR = 16.18). Network toxicology identified five core targets shared across key SOCs: EGFR, ERBB2, TGFB1, PIK3CA, and HSPG2. KEGG enrichment analysis highlighted pathways related to parasitic diseases, leukocyte migration, and endocrine regulation. Molecular docking confirmed high binding affinity between ivermectin components and EGFR (≤ -8.7 kcal/mol). ADMET predictions indicated elevated risks for genotoxicity, ototoxicity, and skin sensitization. Conclusion Ivermectin-associated ADRs manifest across multiple organ systems, which are potentially associated with the modulation of predicted candidate targets including EGFR, ERBB2, TGFB1, PIK3CA, and HSPG2.