Development and Validation of an Approach to Assessing Clinical Relevance of Potential Drug–Drug Interactions Inducing Rare but Serious Adverse Events

Abstract

Evaluating clinical relevance of potential drug–drug interactions is significant for managing safety risks. However, current approaches to the evaluation lack data on rare but serious adverse events. This study aims to develop an approach to assessing clinical relevance of potential drug–drug interactions that induce rare and serious adverse events, and test its performance. In the development, three key dimensions for evaluating clinical relevance were synthesized based on a literature review. A systematic five-step approach was proposed through designated dimensions and discussions within the research team. Subsequently, the approach was applied to patients with depression to validate its ability of demonstrating the dimensions, and exacting data on rare but serious adverse events. The test results showed varying signal intensities among different drug combinations in relation to adverse events including serotonin syndrome, long QT syndrome, and Torsade de Pointes. Advanced age was identified as a confounding factor for the QT prolongation signal. These findings operationalize Dimension one: Probabilities and risk factors for the occurrence of rare and serious adverse events. Besides, in the test, fatality occurred in 22.01% of the cases having drug-triggered QT prolongation. Advancing age was associated with the fatality (odds ratio = 1.03, 95% confidence interval = 1.01–1.07). The findings manifested Dimension two: Magnitude of adverse events and associated factors. Dimension three was achieved by findings of median time-to-onset of fatal serotonin syndrome and QT prolongation, which was one and 8 days, respectively. In summary, the proposed approach demonstrates effects in assessing the clinical relevance of potential drug–drug interactions.