Drug-induced liver injury associated with elexacaftor/tezacaftor/ivacaftor: A pharmacovigilance analysis of the FDA adverse event reporting system (FAERS)

•Using the FDA adverse event reporting system database, ETI and DILI reports were found to be significantly associated (p < 0.05) for all disproportionality measures (PRR, ROR, IC, EGBM, chi-squared).•The ROR for ETI-DILI is greater than that of ∼10 % of the “Most-DILI concern” drugs in the FDA DILIRank dataset.•ETI-DILI reports for people with cystic fibrosis were predominately male, in contrast to patient reports for other drugs and DILI.•“Hospitalization” was the second most common patient outcome for ETI-DILI after "other serious outcomes”.•Most people with cystic fibrosis experienced onset times within 3 months of initiation; however, several occurred prior to 3 months or beyond 1 year, indicating additional monitoring may be prudent. The efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with drug-induced liver injury (DILI). To address this gap, we assessed the real-world risk of DILI associated with ETI through data mining of the FDA adverse event reporting system (FAERS). Disproportionality analyses were conducted on FAERS data from the fourth quarter of 2019 through the third quarter of 2022. Comparative patient demographics, onset time and outcomes for ETI-DILI were also obtained. 452 reports of DILI associated with ETI were found, representing 2.1 % of all adverse event reports for ETI. All disproportionality measures were significant for ETI-DILI at p < 0.05; the reporting odds ratio (ROR) (2.82) was comparable to that of drugs classified by FDA as “Most-DILI concern”. The most notable demographic finding was a male majority (5:4 male to female ratio) for ETI-DILI compared to a female majority (4:5 male to female ratio) for non ETI-DILI. Median ETI-DILI onset time was 50.5 days, and hospitalization was the second most common complication. Using FAERS data, ETI was found to be disproportionately associated with DILI. Future research is needed to investigate the hepatotoxic mechanisms and assess potential mitigation strategies for ETI-induced hepatotoxicity.