In mild to severe cirrhosis, the recommended dose reductions for nifedipine, verapamil, nebivolol, and diltiazem were 44%, 41%, 50%, and 51%, respectively, of healthy doses.
How should doses of antihypertensive drugs be adjusted in patients with varying severities of liver cirrhosis based on pharmacokinetic modeling?
PBPK modeling suggests significant dose reductions are necessary for antihypertensive drugs like nifedipine, verapamil, nebivolol, and diltiazem in patients with liver cirrhosis to match healthy unbound drug exposures.
Absolute Event Rate: 0% vs 0%
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.
Tarek et al. (Thu,) reported a other. In mild to severe cirrhosis, the recommended dose reductions for nifedipine, verapamil, nebivolol, and diltiazem were 44%, 41%, 50%, and 51%, respectively, of healthy doses.