Evaluation of Elexacaftor/Tezacaftor/Ivacaftor-Mediated Drug-Induced Liver Injury Using a Liver-On-Chip Model

Elexacaftor/tezacaftor/ivacaftor (ETI), a cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, has provided great improvements in lung function and well-being for people with CF. The use of ETI has been complicated by reports of rare but significant liver function test elevations in clinical trials and drug-induced liver injury (DILI) in real-world use. Previous research by our group revealed that oxidative stress is the major driver of ETI-mediated DILI, and in silico ETI DILI simulations resulted in elevations of the emerging biomarker glutamine dehydrogenase (GLDH) which match the time course of predicted transaminase elevations. The assessment of emerging biomarkers and therapeutic strategies in a clinically relevant model will spur the development of more effective treatments for ETI-mediated DILI. This study used the human-relevant liver-on-chip model to investigate GLDH as a biomarker and ETI dose reduction and silymarin antioxidant administration as therapeutic strategies for ETI-mediated DILI. We found that GLDH was not as sensitive as ALT and albumin for detecting DILI due to ETI. Dose reduction was a more effective treatment strategy for ETI DILI than silymarin, which did not significantly lower ALT levels.

CFTR modulator; DILI; hepatotoxicity; liver injury; liver‐on‐chip.