The right compound in the right assay at the right time: an integrated discovery DMPK strategy

Abstract

The high rate of attrition during drug development and its associated high research and development (R&D) cost have put pressure on pharmaceutical companies to ensure that candidate drugs going to clinical testing have the appropriate quality such that the biological hypothesis could be evaluated. To help achieve this ambition, drug metabolism and pharmacokinetic (DMPK) science and increasing investment have been deployed earlier in the R&D process. To gain maximum return on investment, it is essential that DMPK concepts are both appropriately integrated into the compound design process and that compound selection is focused on accurate prediction of likely outcomes in patients. This article describes key principles that underpin the contribution of DMPK science for small-molecule research based on 15 years of discovery support in a major pharmaceutical company. It does not aim to describe the breadth and depth of DMPK science, but more the practical application for decision making in real-world situations.

Keywords::

• Compound optimization
• design-make-test-analyze cycles
• human pharmacokinetic and dose predictions
• CNS distribution
• drug-drug interactions
• clearance
• absorption
• metabolites
• transporters

Acknowledgments

The authors acknowledge the contributions of the following people to the manuscript for this article: Ken Grime, Owen Jones, Anna-Lena Ungell, Richard Thompson, and many AstraZeneca DMPK scientists involved in discussions. The authors also thank Jenny Watson (Watson Consulting Services, Chatswood, New South Wales, Australia) for her editorial input to this work.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.