A 20-Year Research Overview: Quantitative Prediction of Hepatic Clearance Using the IVIVE Approach Based on PBPK Modeling and Extended Clearance Concept.

Understanding the "Extended Clearance Concept (ECC)" and establishing a physiologically based pharmacokinetic (PBPK) model are crucial for investigating the impact of changes in transporter and metabolizing enzyme abundance/functions on drug pharmacokinetics in blood and tissues. This mini-review provides an overview of ECC and a PBPK model that includes transporter-mediated uptake processes in the liver. In general, complete in vitro and in vivo extrapolation (IVIVE) poses challenges due to missing factors that bridge the gap between in vitro and in vivo systems. By considering key in vitro parameters, we can capture in vivo pharmacokinetics, a strategy known as the top-down or middle-out approach. We present the latest progress, theory, and practice of the Cluster Gauss-Newton method (CGNM), which is utilized for middle-out analyses. As examples of poor IVIVE, we discuss "albumin-mediated hepatic uptake" and "time-dependent inhibition" of OATP1Bs. The hepatic uptake of highly plasma-bound drugs is more efficient than what can be accounted for by their unbound concentration alone. This phenomenon is referred to as "albumin-mediated" hepatic uptake. IVIVE was improved by measuring hepatic uptake clearance in vitro in the presence of physiological albumin concentrations. Lastly, we demonstrate the application of CGNM-based analysis to the target-mediated drug disposition (TMDD) of bosentan. Incorporating saturable target binding and OATP1B mediated hepatic uptake into the PBPK model enables the consideration of nonlinear kinetics across a wide dose range and the prediction of receptor occupancy over time. Significance Statement There have been multiple instances where researchers' endeavors to unravel the underlying mechanism of poor in vitro-in vivo extrapolation (IVIVE) have led to the discovery of previously undisclosed truths. These include: (i) albumin-mediated hepatic uptake, (ii) the target-mediated drug disposition (TMDD) in small molecules, and (iii) the existence of a trans-inhibition mechanism by inhibitors for OATP1B-mediated hepatic uptake of drugs. Consequently, poor IVIVE and the subsequent inquisitiveness of scientists may serve as a pivotal gateway to uncover hidden mechanisms.