Quantitative Systems Toxicology Model Predicts Obeticholic Acid‐Associated Liver Injury in Metabolic Dysfunction‐Associated Steatotic Liver Disease

Obeticholic acid (OCA), a synthetic analog of chenodeoxycholic acid, was approved in 2016 for the treatment of primary biliary cholangitis. Early clinical trials revealed elevated liver biomarkers in healthy subjects receiving supratherapeutic OCA doses (100–250 mg). OCA was also evaluated as a treatment for metabolic dysfunction‐associated steatotic liver disease (MASLD) but was not approved by the FDA due to liver safety concerns. In this in silico study, we investigated mechanisms of OCA‐associated liver injury in virtual healthy and MASLD populations receiving supratherapeutic and therapeutic (10–25 mg) doses, respectively. OCA and metabolite exposures in plasma, sinusoidal blood, liver, and gut compartments were simulated using a physiologically based pharmacokinetic model. In the virtual MASLD population, exposures were increased 2‐, 5‐, and 10‐fold in plasma, sinusoidal, and/or liver compartments relative to baseline. Mechanistic parameters relevant to OCA‐mediated liver injury, including bile acid transporter inhibition and mitochondrial dysfunction, were incorporated into the DILIsym model. Predicted liver injury was reported as evaluation of drug‐induced serious hepatotoxicity (eDISH) plots, and elevations in alanine aminotransferase, aspartate aminotransferase, and total hepatic bile acids. DILIsym simulations recapitulated liver biomarker elevations observed at supratherapeutic OCA doses in healthy subjects and predicted biomarker increases in the MASLD population under conditions of 5‐ and 10‐fold increased exposures relevant to this population. Bile acid transporter inhibition alone reproduced simulated biomarker elevations, whereas mitochondrial uncoupling alone predicted increased biomarkers only at the highest exposures. Results suggest that DILIsym modeling would have predicted the liver safety concerns that led to withdrawal of OCA from the US market.