Quantitative Systems Toxicology Predicts Ivacaftor‐Induced Oxidative Stress Contributes to <scp>CFTR</scp> Modulator Hepatotoxicity

Cystic fibrosis (CF) is a chronic hereditary disease that affects tens of thousands of people worldwide. The introduction of CFTR modulator therapies such as elexacaftor/tezacaftor/ivacaftor (ETI) has significantly improved the quality of life of people with CF. However, ETI has been shown in clinical trials to cause elevations in liver enzymes, and real-world cases of drug-induced liver injury (DILI) have also been reported. The mechanism of ETI-mediated DILI is currently unknown, hindering the development of more effective mitigation strategies for this adverse reaction. Through in vitro assays and quantitative systems toxicology modeling using DILIsym, this study revealed that ivacaftor contributed most significantly to ETI-mediated DILI, primarily via reactive oxygen species production, resulting in mitochondrial dysfunction due to electron transport chain inhibition. DILIsym modeling also predicted liver enzyme elevations following daily dosing of ETI at a comparable frequency (6.0%) to that of clinical data (8.0%). Simulations of the therapeutic effects of DILI mitigation strategies for ETI showed that dose reduction and antioxidant administration may significantly reduce the frequency of liver enzyme elevations due to ETI.