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

Abstract

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.

Fig. 1

The importance of considering time of co-exposure at an early stage in the process once a potential alert is retrieved. DDI drug–drug interaction, ICSR individual case safety report

Fig. 2

Choice of comparator. CI confidence interval, ICSR individual case safety report, LB lower bound, ROR reporting odds ratio, UB upper bound

Fig. 3

Example of flex point in cumulative reporting. The x-axis represents the co-exposure time of drug A and drug B expressed in days, while the y-axis represents the cumulative incidence of reporting a certain co-exposure time for a specific adverse event in each individual case safety report

Fig. 4

Venn diagrams of type of triplets reported as frequencies (percentages) and retrieved considering those that were identified as a disproportionality signal for the temporal plausibility assessment using our method. Definitions of evidence and severity levels are those reported by Kontsioti et al. [10] in their work: evidence—evidence level associated with the drug–drug interaction as shown in Micromedex; severity—severity level associated with the drug–drug interaction as shown in Micromedex

Fig. 5

Cumulative reporting. Each graph represents the cumulative reporting of one triplet where drug A is analysed when reported (or not) in co-exposure with drug B. The x-axis represents the co-exposure time of drug A and drug B expressed in days, while the y-axis represents the cumulative incidence of reporting a certain co-exposure time for a specific adverse event in each individual case safety report