Background: DMPK data and knowledge are critical in maximising the probability of developing successful
drugs via the application of in silico, in vitro and in vivo approaches in drug discovery.
Methods: The evaluation, optimisation and prediction of human pharmacokinetics is now a mainstay within drug
discovery. These elements are at the heart of the ‘right tissue’ component of AstraZeneca’s ‘5Rs framework’ which,
since its adoption, has resulted in increased success of Phase III clinical trials. With the plethora of DMPK related
assays and models available, there is a need to continually refine and improve the effectiveness and efficiency of
approaches best to facilitate the progression of quality compounds for human clinical testing.
Results: This article builds on previously published strategies from our laboratories, highlighting recent discoveries
and successes, that brings our AstraZeneca Oncology DMPK strategy up to date. We review the core aspects of
DMPK in Oncology drug discovery and highlight data recently generated in our laboratories that have influenced our
screening cascade and experimental design. We present data and our experiences of employing cassette animal PK,
as well as re-evaluating in vitro assay design for metabolic stability assessments and expanding our use of freshly
excised animal and human tissue to best inform first time in human dosing and dose escalation studies.
Conclusion: Application of our updated drug-drug interaction and central nervous system drug exposure strategies
are exemplified, as is the impact of physiologically based pharmacokinetic and pharmacokinetic-pharmacodynamic
modelling for human predictions.