Date of Award
Summer 2024
Document Type
Open Access Dissertation
Department
College of Pharmacy
First Advisor
Michael Wyatt
Abstract
Drug repurposing has emerged as an innovative strategy to identify new therapeutic uses for existing medications. However, with few notable exceptions, repurposing existing drugs has limited overall success, often failing in randomized controlled trials (RCTs) due to inadequate treatment efficacy in new clinical settings. To improve success rates, I propose a framework titled REMIDY: Retrospective and Experimental Methods Integration for Drug DiscoverY. The REMIDY framework incorporates retrospective claims analysis into the drug discovery process. I demonstrate that retrospective analysis can leverage extensive administrative and clinical data to address translational gaps between pre-clinical experimental models and RCTs. For example, pre-clinical experimental results identified fluoxetine and fluvoxamine as direct NLRP3 inhibitors. NLRP3 inhibition is also established using pre-clinical models as a possible pharmacologic target for age-related macular degeneration (AMD). Based on the preclinical results, these medications were investigated for their potential to reduce the risk of age-related macular degeneration (AMD). Retrospective claims analysis indicated a lower hazard of AMD among fluoxetine users, highlighting its potential for repurposing. To test the potential of NLRP3 as a pharmacologic target for AMD, retrospective claims analysis was employed to demonstrate that medications like bisphosphonates, which preclinical studies have shown to increase NLRP3 expression, also increased the risk of developing AMD. Fluoxetine and fluvoxamine were also evaluated for their potential to inhibit NLRP3 in other contexts, specifically for preventing cisplatin-induced ototoxicity. While claims data suggested a protective effect, audiologic test results did not support this finding, underscoring the need for robust evidence from both preclinical and retrospective analyses before proceeding to costly RCTs. This approach allows for the assessment of various medications, providing evidence to support or refute their potential effectiveness. For instance, lovastatin showed promise in preventing cisplatin-induced hearing loss based on preclinical and audiologic data, making it a strong candidate for RCT evaluation. Grounding retrospective database analyses in robust experimental evidence ensures these studies can generate evidence for repurposing, not simply associations. Moreover, retrospective analysis fills an intermediate role between preclinical laboratory results and RCTs. This integrated approach can improve the prioritization of medications for RCTs, in hopes of greater success rates.
Rights
© 2024, Joseph Magagnoli
Recommended Citation
Magagnoli, J.(2024). Improving Drug Repurposing Success: Integrating Large Database Claims Analysis in Drug Discovery. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7959