Mitigating permeability-mediated risks in drug discovery

Abstract

Importance of the field: Adequate permeability is essential for good oral absorption and proper interpretation of pharmacokinetic and pharmacological data. Permeability-limiting absorption and distribution, however, are complex phenomena involving multiple mechanisms and organs ranging from gastro-intestine, liver, kidney to BBB, while the options for pharmaceutical improvement of permeability are quite limited.

Areas covered in this review: In this article, the comprehensive in silico, in vitro and in vivo/ex vivo/in situ tools to assess permeability are reviewed, alongside their advantages and limitations. 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.

What the reader will gain: The integrated strategy to properly utilize existing permeability tools for mitigating the permeability-related absorption or safety risks at the different stages of drug discovery and development processes is presented.

Take home message: It is critical to utilize the comprehensive in silico, in vitro and in vivo/ex vivo tools to dial out permeability issues in early drug discovery, ensuring the right questions to be addressed using the right tools at the right time.

Keywords::

• absorption
• ADME
• BBB
• BCS
• bioavailability
• Caco-2 ISIVIVC
• PAMPA
• permeability
• P-gp
• transporter

Acknowledgements

The authors thank L Bell and G Pan for critical review of the manuscript. Discussions with and supporting information from X Lin, L Zhou and W Egan are acknowledged.

Notes

This box summarises key points contained in the article.