Detecting drug-drug interactions between therapies for COVID-19 and concomitant medications through the FDA adverse event reporting system

Abstract

Background: COVID-19 patients with underlying medical conditions are vulnerable to drug-drug interactions (DDI) due to the use of multiple medications. We conducted a discovery-driven data analysis to identify potential DDIs and associated adverse events (AEs) in COVID-19 patients from the FDA Adverse Event Reporting System (FAERS), a source of post-market drug safety. Materials and Methods: We investigated 18,589 COVID-19 AEs reported in the FAERS database between 2020 and 2021. We applied multivariate logistic regression to account for potential confounding factors, including age, gender, and the number of unique drug exposures. The significance of the DDIs was determined using both additive and multiplicative measures of interaction. We compared our findings with the Liverpool database and conducted a Monte Carlo simulation to validate the identified DDIs. Results: Out of 11,337 COVID-19 drug-Co-medication-AE combinations investigated, our methods identified 424 signals statistically significant, covering 176 drug-drug pairs, composed of 13 COVID-19 drugs and 60 co-medications. Out of the 176 drug-drug pairs, 20 were found to exist in the Liverpool database. The empirical p-value obtained based on 1,000 Monte Carlo simulations was less than 0.001. Remdesivir was discovered to interact with the largest number of concomitant drugs (41). Hydroxychloroquine was detected to be associated with most AEs (39). Furthermore, we identified 323 gender- and 254 age-specific DDI signals. Conclusion: The results, particularly those not found in the Liverpool database, suggest a subsequent need for further pharmacoepidemiology and/or pharmacology studies.

Keywords: COVID-19; FAERS; additive interaction; discovery-driven; drug-drug interactions; hypothesis generation; logistic regresion; multiplicative interaction.

FIGURE 1

A measure of additive interaction between a COVID-19 drug and a co-medication on a targeted AE.

FIGURE 2

Drug-drug interaction network. The size of a node is proportional to the number of neighboring drugs, while the color corresponds to the ATC 1st level. The width of an edge is proportional to the number of unique AEs, while its color indicates whether or not an interaction was documented in the Liverpool database.

FIGURE 3

(A) The number of significant DDIs. (B) The number of unique co-medications that caused interactions with the COVID-19 drugs. (C) The number of unique AEs.

FIGURE 4

Heatmap depicting statistically significant associations between the COVID-19 drugs (on the bottom) and the co-medications (clustered by ATC 1st level, on the left). The cells were colored white to red according to the number of AEs present (grey if there was insufficient data in the FAERS database to investigate associations). Asterisks were used to denote the DDIs in the Liverpool database (*: potential weak interaction, **: potential interaction, and ***: do not co-administer).

FIGURE 5

Heat map depicting statistically significant associations between the COVID-19 drugs (on the bottom) and MedDRA HLTs (clustered by MedDRA SOC, on the left). The cells were colored white to red according to the number of drugs in the co-medications that caused an AE when combined with a drug in the COVID-19 drugs (grey if there was insufficient data in the FAERS database to investigate associations).