Drug-induced liver injury associated with elexacaftor/tezacaftor/ivacaftor from the FDA Adverse Event Reporting System (FAERS)

IntroductionThe 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). MethodsDisproportionality 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. Results452 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) was comparable to that of drugs classified by FDA as "Most-DILI concern". The most notable demographic finding was a male majority for ETI-DILI compared to a female majority for non ETI-DILI. Median ETI-DILI onset time was 50.5 days, and hospitalization was the second most common complication. ConclusionUsing FAERS data, ETI was found to be disproportionality associated with DILI. Future research is needed to investigate the hepatotoxic mechanisms and assess potential mitigation strategies for ETI-induced hepatotoxicity. Article HighlightsO_LIUsing the FDA Adverse Event Reporting System database, ETI and DILI were found to be significantly associated (p < 0.05) for all disproportionality measures (PRR, ROR, IC, EGBM, Yates chi-squared). C_LIO_LIThe ROR for ETI-DILI is greater than that of many "Most-DILI concern" drugs in the FDA DILIRank dataset but is not within the top 20 drugs associated with DILI. C_LIO_LIPatient reports for ETI-DILI were predominately male, in contrast to patient reports for other drugs and DILI. C_LIO_LI"Hospitalization" was the second most common patient outcome for ETI-DILI after "other serious outcomes". C_LIO_LIMost patients had onset times within 3 months of initiation, several patients had an onset time greater than 1 year. C_LIO_LIOnset times indicate that liver function test monitoring should be initiated earlier than 3 months and potentially extend beyond 1 year in some patients. C_LI