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

INTRODUCTION: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.