DISPROPORTIONALITY ANALYSIS AND MULTIMODAL GENETIC ASSESSMENT OF PAPILLEDEMA ASSOCIATED WITH PROTEASOME INHIBITORS
Author(s)
Ritesh Giri, PharmD, Clinical Pharmacy Residency (Oncology)1, Tania V. Abraham, PharmD2, Priya Anand, PharmD1, Likitha YV, PharmD1, Prizvan L. D Souza, PharmD2, Ganesan Rajalekshmi Saraswathy, PhD1;
1M.S. Ramaiah University Of Applied Sciences, Department of Pharmacy Practice, Faculty of Pharmacy, Bengaluru, India, 2M.S. Ramaiah Memorial Hospital, Department of Clinical Pharmacy, Bengaluru, India
1M.S. Ramaiah University Of Applied Sciences, Department of Pharmacy Practice, Faculty of Pharmacy, Bengaluru, India, 2M.S. Ramaiah Memorial Hospital, Department of Clinical Pharmacy, Bengaluru, India
OBJECTIVES: Proteasome Inhibitors (PI) are widely used in treating multiple myeloma and certain lymphomas. However, potential ophthalmic adverse events may be underreported. This study aimed at evaluating an association between papilledema and PI by detecting pharmacovigilance safety signals using disproportionality analysis and exploring plausible mechanisms through bioinformatics and computational modelling.
METHODS: Adverse events associated with PI were extracted from the FAERS database from 2003-2025. Signal detection was performed using Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Chi-square analysis. Genes associated with both, PI and papilledema, were examined using Therapeutic Target Database (TTD), BindingDB, Swiss Target Prediction, UniProt, DrugBank, GeneCards, MalaCards, NCBI, and Comparative Toxicogenomics Database (CTD). Overlapping targets were identified through a Venn diagram. Protein-protein interaction networks were constructed using the STRING database. Key compounds and hub targets were prioritised for molecular docking using Chimera and AutoDock Vina, while functional enrichment analyses (GO and KEGG) were conducted using Metascape and Cytoscape.
RESULTS: A total of 1,962 signals were identified, of which 58 papilledema cases were associated with Bortezomib (n=35), Carfilzomib (n=10), and Ixazomib (n=13). Disproportionality analysis showed PRRs of 3.52, 3.38, and 3.21, respectively. Additionally, identical ROR values were obtained, indicating a positive safety signal. Systematic target identification revealed 20 common genes across the three drugs, of which seven overlapped with papilledema-related targets. Among these, PIK3CA exhibited significant docking for Bortezomib (-8.4 kcal/mol), Carfilzomib (-9.8 kcal/mol), and Ixazomib (-8.0 kcal/mol). Further, network analysis and pathway enrichment implied that proteasome inhibition may sustain PI3K-Akt signalling, contributing to stress-related autophagy, astrocyte swelling, axonal transport dysfunction, and VEGF-associated vascular permeability at the optic nerve head, eventually promoting optic disc edema.
CONCLUSIONS: This study identified a potential association between PI and papilledema through disproportionality analysis and comprehensive genetic assessment. Although further clinical research is crucial to verify this corroboration, healthcare providers are opined to be vigilant.
METHODS: Adverse events associated with PI were extracted from the FAERS database from 2003-2025. Signal detection was performed using Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Chi-square analysis. Genes associated with both, PI and papilledema, were examined using Therapeutic Target Database (TTD), BindingDB, Swiss Target Prediction, UniProt, DrugBank, GeneCards, MalaCards, NCBI, and Comparative Toxicogenomics Database (CTD). Overlapping targets were identified through a Venn diagram. Protein-protein interaction networks were constructed using the STRING database. Key compounds and hub targets were prioritised for molecular docking using Chimera and AutoDock Vina, while functional enrichment analyses (GO and KEGG) were conducted using Metascape and Cytoscape.
RESULTS: A total of 1,962 signals were identified, of which 58 papilledema cases were associated with Bortezomib (n=35), Carfilzomib (n=10), and Ixazomib (n=13). Disproportionality analysis showed PRRs of 3.52, 3.38, and 3.21, respectively. Additionally, identical ROR values were obtained, indicating a positive safety signal. Systematic target identification revealed 20 common genes across the three drugs, of which seven overlapped with papilledema-related targets. Among these, PIK3CA exhibited significant docking for Bortezomib (-8.4 kcal/mol), Carfilzomib (-9.8 kcal/mol), and Ixazomib (-8.0 kcal/mol). Further, network analysis and pathway enrichment implied that proteasome inhibition may sustain PI3K-Akt signalling, contributing to stress-related autophagy, astrocyte swelling, axonal transport dysfunction, and VEGF-associated vascular permeability at the optic nerve head, eventually promoting optic disc edema.
CONCLUSIONS: This study identified a potential association between PI and papilledema through disproportionality analysis and comprehensive genetic assessment. Although further clinical research is crucial to verify this corroboration, healthcare providers are opined to be vigilant.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
EPH209
Topic
Epidemiology & Public Health
Topic Subcategory
Safety & Pharmacoepidemiology
Disease
SDC: Neurological Disorders, SDC: Oncology, SDC: Sensory System Disorders (Ear, Eye, Dental, Skin), STA: Personalized & Precision Medicine