A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein‐bound drugs and impact of errors in plasma protein binding

This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration‐time profiles for 22 highly protein‐bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood:plasma ratio. Clearance was predicted with a well‐stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration‐time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2‐fold error was obtained for terminal elimination half‐life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration‐time curve (AUC0‐t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low‐clearance compounds, and in Vss prediction for high‐volume neutral drugs. For high‐volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. This article is protected by copyright. All rights reserved.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research