An Absolute Abundance-Function Approach for Fully Mechanistic Drug Transporter IVIVE

An Absolute Abundance-Function Approach for Fully Mechanistic Drug Transporter IVIVEM. Harwood 11 University of ManchesterGut Barrier Group, Inflammation & Repair, Clinical Sciences Building, University of Manchester, M6 8HDThe use of whole body physiologically-based pharmacokinetic models (PBPK) models linked with in vitro-in vivoextrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become commonplace within thepharmaceutical industry and is used for regulatory submissions. PBPK models contain the masses and volumes of multipleorgans, together with the organ-specific expression, and activity of pharmacokinetically important proteins, includingtransporters. In the last several years, the development of high powered analytical technology and antibody-based techniqueshave provided the capability to quantitate low abundance proteins such as transporters in mammalian tissues and in vitroexperimental systems. The majority of PBPK models to date have predicted drug pharmacokinetics using relative expressionapproaches for transporter proteins. Yet, incorporation of the absolute abundances of transporters into IVIVE-PBPK modelscan potentially enhance the modeling of transporter kinetics by IVIVE-PBPK models.Herein, approaches to utilize a combination of the absolute abundance and activity of transporter proteins in IVIVE-PBPKmodels will be described, including;1. The generation of IVIVE scaling factors to bridge mechanistic gaps between the in vitro experimental models used togenerate kinetic data and the human in vivo system.2. The incorporation of abundances into organs and their scaling within these organs using tissue based scaling factors.3. A focus on the challenges and pitfalls to implementing the available abundance data into PBPK models.At present, the incorporation of absolute abundance data into an IVIVE-PBPK approach requires careful consideration.Nonetheless, these approaches can provide an enhanced understanding of transporter abundance-function relationships inorder to predict the impact of transporters on drug disposition.