Mitigating Permeability and Absorption Risks in Drug Discovery

Adequate permeability is essential for good oral absorption and proper interpretation of pharmacokinetic and pharmacological data. Permeability-limiting absorption, however, is a complex phenomenon involving multiple mechanisms and organs ranging from gastro-intestine, liver, kidney to brain blood barrier, but the options for pharmaceutical improvement of permeability are quite limited. In this article, the comprehensive in silico, in vitro and in vivo/ex vivo/in situ tools to assess permeability were reviewed, alongside their advantages and limitations. The integrated strategy to mitigate the permeability-related absorption or safety risks at the different stages of drug discovery and development processes was presented. Several key points relating to the in vivo predictive impact of in vitro permeability tools and the caveats when dealing with challenging discovery compounds were also addressed, using drug discovery cases and statistics in Novartis