Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and PBPK Modeling Approaches

Abstract

This white paper examines recent progress, applications and challenges in predicting unbound and total tissue and intra/subcellular drug concentrations using in vitro and preclinical models, imaging techniques and physiologically-based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions and case studies illustrate the application of different types of data in drug development to support modeling and decision making for compounds with transporter-mediated disposition, and likely disconnects between tissue and systemic drug exposure. The goals of this manuscript are to illustrate current best practices and outline practical strategies for selecting appropriate in vitro and in vivo experimental methods to estimate or predict tissue and plasma concentrations, and to use these data in the application of PBPK modeling for human PK, efficacy and safety assessment in drug development.