Using Physiologically Based Pharmacokinetic Modeling and Simulations to Predict Antihypertensive Drug Doses in Cirrhotic Patients

Abstract

Liver cirrhosis can alter drug pharmacokinetics, often requiring dose adjustments. Physiologically based pharmacokinetic (PBPK) modeling aids in predicting these pharmacokinetic changes in cirrhosis patients. This study developed and validated PBPK models for multiple antihypertensive drugs to predict dosing across varying severities of cirrhosis. Models were initially validated in healthy volunteers, then adjusted to incorporate cirrhosis-specific pathophysiological changes. Predicted results (area under the curve [AUC] and plasma maximum concentration [Cmax]) showed good agreement with clinical data (within 2-fold). The models were further used to simulate untested cirrhotic populations and to estimate unbound plasma AUC across different disease stages, and the results were compared with the healthy population. The model predicted that the healthy doses of nifedipine 20 mg three times daily (TID), verapamil 80 mg TID, nebivolol 10 mg once daily, and diltiazem 60 mg TID should be adjusted to 44%, 41%, 49.8%, and 51% of these doses, respectively, in the mild cirrhosis population. For moderate cirrhosis, the predicted reductions were to 21%, 25%, 29.8%, and 39%, respectively. In severe cirrhosis, greater reductions to 9.9%, 19%, 12.3%, and 26%, respectively, were necessary to achieve the same unbound drug exposures as in healthy subjects. Among the studied drugs, nifedipine was the most affected and diltiazem was the least affected by cirrhosis, highlighting variability in hepatic impact across antihypertensive drugs. In the absence of dedicated clinical trials in cirrhosis for these drugs, validated PBPK models offer evidence-based insights to support clinicians in evaluating antihypertensive dosing options.