Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches

Clin Pharmacol Ther. 2018 Nov;104(5):865-889. doi: 10.1002/cpt.1183. Epub 2018 Sep 12.


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 article 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 pharmacokinetic (PK), efficacy, and safety assessment in drug development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Assay*
  • Cells, Cultured
  • Drug Development / methods*
  • Humans
  • In Vitro Techniques*
  • Membrane Transport Proteins / metabolism*
  • Models, Biological*
  • Molecular Imaging*
  • Pharmaceutical Preparations / blood
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*
  • Reproducibility of Results
  • Risk Assessment
  • Tissue Distribution


  • Membrane Transport Proteins
  • Pharmaceutical Preparations