Timing Matters: A Machine Learning Method for the Prioritization of Drug-Drug Interactions Through Signal Detection in the FDA Adverse Event Reporting System and Their Relationship with Time of Co-exposure.

INTRODUCTION: Current drug-drug interaction (DDI) detection methods often miss the aspect of temporal plausibility, leading to false-positive disproportionality signals in spontaneous reporting system (SRS) databases. OBJECTIVE: This study aims to develop a method for detecting and prioritizing temporally plausible disproportionality signals of DDIs in SRS databases by incorporating co-exposure time in disproportionality analysis. METHODS: The method was tested in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The CRESCENDDI dataset of positive controls served as the primary source of true-positive DDIs. Disproportionality analysis was performed considering the time of co-exposure. Temporal plausibility was assessed using the flex point of cumulative reporting of disproportionality signals. Potential confounders were identified using a machine learning method (i.e. Lasso regression). RESULTS: Disproportionality analysis was conducted on 122 triplets with more than three cases, resulting in the prioritization of 61 disproportionality signals (50.0%) involving 13 adverse events, with 61.5% of these included in the European Medicine Agency's (EMA's) Important Medical Event (IME) list. A total of 27 signals (44.3%) had at least ten cases reporting the triplet of interest, and most of them (n = 19; 70.4%) were temporally plausible. The retrieved confounders were mainly other concomitant drugs. CONCLUSIONS: Our method was able to prioritize disproportionality signals with temporal plausibility. This finding suggests a potential for our method in pinpointing signals that are more likely to be furtherly validated.

Exploring the impact of co-exposure timing on drug-drug interactions in signal detection through spontaneous reporting system databases: a scoping review.

INTRODUCTION: Drug-drug interactions (DDIs) are defined as the pharmacological effects produced by the concomitant administration of two or more drugs. To minimize false positive signals and ensure their validity when analyzing Spontaneous Reporting System (SRS) databases, it has been suggested to incorporate key pharmacological principles, such as temporal plausibility. AREAS COVERED: The scoping review of the literature was completed using MEDLINE from inception to March 2023. Included studies had to provide detailed methods for identifying DDIs in SRS databases. Any methodological approach and adverse event were accepted. Descriptive analyzes were excluded as we focused on automatic signal detection methods. The result is an overview of all the available methods for DDI signal detection in SRS databases, with a specific focus on the evaluation of the co-exposure time of the interacting drugs. It is worth noting that only a limited number of studies (n = 3) have attempted to address the issue of overlapping drug administration times. EXPERT OPINION: Current guidelines for signal validation focus on factors like the number of reports and temporal association, but they lack guidance on addressing overlapping drug administration times, highlighting a need for further research and method development.