S3 Tissue Transporter Drug-Drug Interactions: Safety/Efficacy Concerns Not Readily Apparent from Systemic Exposure

Aleksandra Galetin , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom

Transporter-mediated drug-drug interactions (DDIs) often involve interplay between multiple transporters and/or enzymes in different tissues. In many cases these complex DDIs result in differential effect on systemic and tissue drug exposure with potential consequences on either drug safety and/or efficacy. This presentation will focus on the application of physiologically-based pharmacokinetic (PBPK) modelling as a translational tool to address this disconnect and gain mechanistic insight into interplay of multiple processes. Effect of different clinical scenarios (transporter DDI, genetic polymorphism, hepatic/renal impairment) on the drug exposure in the liver and renal proximal tubule will be illustrated for a number of drugs including simvastatin, digoxin and obeticholic acid. Challenges with respect to verification of such PBPK model-predicted changes in tissue exposure and appropriate use of clinical data for reverse translation will be discussed.