Neural dysfunction, inflammatory disorder, and metabolic interference feature in amantadine-related adverse drug...

Adverse drug events (ADEs) related to amantadine gradually increase as the drug is broadly acknowledged for remission of Parkinson's disease or Parkinsonism. The ADEs vary according to the affected organs and the potential mechanisms remain elusive.

We mined data from the FAERS Database and employed network toxicology to appraise amantadine-related ADEs and dissect the toxicological mechanisms.

We found 1,917 ADE reports relevant to amantadine that embodied 1,871 intense-signal ADEs (implicating 134 preferred terms (PTs)). Of those PTs, 69 were undeclared in current amantadine insert. System organ class (SOC) term-based analysis showed that PDGFRB, STAT3, and PRKCD, as well as the enriched pathways such as Neuroactive ligand - receptor interaction and Toll-like receptor signaling pathway were instrumental in amantadine-related Death outcome. Toxicological analysis for the representative undeclared ADEs showed that the toxic targets like STAT3, MAPK1, and CYP3A4 played central roles in amantadine toxicity and adverse events. Molecular docking revealed high-affinity binding of amantadine to MAPK1, MAPK3, HSP90AA1, CYP3A4, and CYP2C19 which were involved in neural function, inflammation, and metabolism.

The mechanisms underlying amantadine-related ADEs allow new insights into pharmacovigilance for amantadine use.