Predicting Systemic and Liver Bosentan Exposure Using Physiologically-Based Pharmacokinetic Modeling.

Area of Science:

• Pharmacology
• Toxicology
• Biomedical Engineering

Background:

• Bosentan is an oral medication for pulmonary arterial hypertension (PAH) with a black-box warning for liver injury risk.
• Understanding bosentan's mechanisms of liver injury is crucial for accurate risk assessment.
• Integrating mechanistic data with hepatic bosentan concentrations can enhance risk evaluation.

Purpose of the Study:

• To develop a physiologically-based pharmacokinetic (PBPK) model to predict hepatic disposition and intrahepatic exposure of bosentan.
• To enable a more dynamic and relevant risk assessment of bosentan-induced liver injury.

Main Methods:

• Designed a workflow for PBPK model development focusing on bosentan's hepatic disposition.
• Utilized clinical plasma and excretion data to refine hepatic clearance estimation.
• Validated model predictions against observed systemic and excretion data.

Main Results:

• The PBPK model accurately predicted bosentan's systemic circulation and excretion.
• Model-derived intrinsic hepatic clearance aligned with clinical study findings.
• Simulated steady-state unbound hepatic bosentan exposure ranged from 1.65 to 34.1 ng/mL.
• The ratio of simulated unbound liver to plasma concentrations varied between 0.80 and 2.93.

Conclusions:

• A bosentan PBPK model was successfully developed, accurately predicting hepatic disposition.
• The model can predict hepatic bosentan exposure, linking in vitro toxicological findings to in vivo effects.
• This tool assists in a more comprehensive risk assessment of bosentan-induced liver injury.