A Mechanistic Physiologically Based Pharmacokinetic (PBPK) modeling approach for fexofenadine: predictive pharmacokinetic insights in humans.

Abstract

The physiologically based pharmacokinetic (PBPK) modeling is an in-silico technique that determines drug pharmacokinetics (PK) by considering blood circulation and tissue composition within the body. Fexofenadine is an H₁ receptor antagonist drug recommended for treating seasonal allergic rhinitis and chronic idiopathic urticaria. This study aimed to build a PBPK model of fexofenadine to predict its systemic exposure in healthy, diseased, and pediatric populations. The modeling process commenced with a meticulous literature review to collect pertinent PK data on fexofenadine, which was then consolidated into the PK-Sim simulator to develop a drug-specific model in the healthy population. The model was then extrapolated to patients with chronic kidney disease (CKD) and pediatrics by employing disease and age-related physiological variations. Visual predictive checks were executed to substantiate the model's accuracy, along with the computation of observed-to-predicted ratios (R_Obs/Pre), average fold error (AFE), and absolute average fold error (AAFE). The developed PBPK model successfully predicted fexofenadine's PK with AFE values of 0.98, 0.58, and 1.21 for CL/F in healthy, diseased, and pediatric populations, which were confined within a two-fold error range. Furthermore, box-and-whisker plots were generated to critically analyze drug concentration at varying stages of CKD. The presented model offers indispensable insights that may assist clinicians in determining dosing strategies in patients with kidney disease.