Pharmacokinetics of CYP2C19- and CYP3A4-Metabolized Drugs in Cirrhosis Using a Whole-Body PBPK Approach
Abstract
Background/Objectives: Cirrhosis significantly alters physiological function and drug metabolism, particularly for medications primarily metabolized by CYP2C19 and CYP3A4. This study aims to establish a physiologically based pharmacokinetic (PBPK) modelling framework capable of predicting pharmacokinetic changes across different stages of cirrhosis, and to determine optimal dosing regimens that achieve drug exposure levels comparable to those in healthy individuals. Methods: We constructed a physiologically based pharmacokinetic (PBPK) model that incorporates six drugs, including omeprazole, lansoprazole, midazolam, ondansetron, verapamil, and alfentanil, which are metabolized primarily by CYP2C19 or CYP3A4. The pharmacokinetics of these drugs following oral or injectable administration were simulated in 1000 virtual healthy subjects, and the PBPK model was validated using clinical data. The model was further adapted to account for physiological changes in cirrhotic patients, extending its application to a population of 1000 virtual patients with liver cirrhosis. Results: Most observed data fell within the 5th and 95th percentiles of the virtual patient simulation results. Additionally, for most simulations, the area under the concentration-time curve (AUC) and peak concentration (Cmax) were within 0.5- to 2-fold of the observed values. Sensitivity analysis indicated that the reduced expression of metabolizing enzymes increased plasma concentrations of drugs, which was a…
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