Overcoming the shortcomings of the extended-clearance concept: a framework for developing a physiologically-based pharmacokinetic (PBPK) model to select drug candidates involving transporter-mediated clearance.

Human pharmacokinetic (PK) prediction can be a significant challenge to drug candidates undergoing transporter-mediated clearance, when only animal data and in vitro human parameters are available in the drug discovery stage.The extended clearance concept (ECC) that incorporates the processes of hepatic uptake, passive diffusion, metabolism and biliary secretion has been adapted to determine the rate-determining process of hepatic clearance and drug-drug interactions (DDIs). However, since the ECC is derived from the well-stirred model and does not consider the liver as a drug distribution organ to reflect the time-dependent variation of drug concentrations between the liver and plasma, it can be misused for compound selection in drug discovery.The PBPK model consists of a set of differential equations of drug mass balance, and can overcome the shortcomings of the ECC in predicting human PK. The predictability, relevance and reliability of the model and the scaling factors for IVIVE must be validated using either the measured liver concentrations or DDI data with known transporter inhibitors, or both, in monkeys. A human PBPK model that incorporates in vitro human data and SFs obtained from the validated monkey PBPK model can be used for compound selection in the drug discovery phase.