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Updated: Jun 24, 2026
07:03
In Vitro Modeling of Fat Deposition in Metabolic Dysfunction-Associated Steatotic Liver Disease
Published on: July 19, 2024
Quantitative Systems Toxicology Model Predicts Obeticholic Acid-Associated Liver Injury in Metabolic
Abigail K Mayo1, James J Beaudoin2, Jeffrey L Woodhead2
1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Clinical Pharmacology and Therapeutics
|June 22, 2026
Summary
Obeticholic acid (OCA) can cause liver injury, especially in MASLD patients. In silico modeling suggests bile acid transporter inhibition is a key mechanism, potentially predicting safety concerns before clinical trials.
Area of Science:
- Pharmacology
- Toxicology
- Computational Biology
Background:
- Obeticholic acid (OCA) is approved for primary biliary cholangitis but has shown liver safety concerns.
- OCA was investigated for metabolic dysfunction-associated steatotic liver disease (MASLD) but faced FDA rejection due to hepatotoxicity.
- Understanding OCA's liver injury mechanisms is crucial for patient safety and drug development.
Purpose of the Study:
- To investigate the mechanisms of OCA-induced liver injury in silico.
- To assess OCA's safety profile in virtual healthy and MASLD populations.
- To evaluate the predictive capability of DILIsym modeling for OCA hepatotoxicity.
Main Methods:
- A physiologically based pharmacokinetic model simulated OCA and metabolite exposures in virtual populations.
- The DILIsym model incorporated mechanistic parameters like bile acid transporter inhibition and mitochondrial dysfunction.
- Liver injury was predicted using eDISH plots and elevations in liver biomarkers (ALT, AST, total hepatic bile acids).
Main Results:
- Simulations recapitulated observed liver biomarker elevations in healthy subjects at supratherapeutic OCA doses.
- Increased OCA exposures in the virtual MASLD population predicted significant biomarker increases.
- Bile acid transporter inhibition alone explained simulated biomarker elevations, while mitochondrial uncoupling had a lesser effect.
Conclusions:
- DILIsym modeling accurately predicted OCA-associated liver biomarker elevations in healthy and MASLD virtual populations.
- Bile acid transporter inhibition appears to be a primary driver of OCA-induced liver injury.
- In silico DILIsym modeling could have foreseen the liver safety concerns leading to OCA's market withdrawal.
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