posted on 2024-02-20, 10:04authored byEmile P. Chen, Shayoni Dutta, Ming-Hsun Ho, Michael P. DeMartino
While
poor translatability of preclinical efficacy models
can be
responsible for clinical phase II failures, misdefinition of the optimal
PK properties required to achieve therapeutic efficacy can also be
a contributing factor. In the present work, the pharmacological dependency
of PK end points in driving efficacy is demonstrated for six common
pharmacological processes via model-based analysis. The analysis shows
that the response is driven by multiple pharmacology-specific PK end
points that change with how the response is defined. Moreover, the
results demonstrate that the most important chemical structural features
influencing response are specific to both target and downstream pharmacology,
meaning the design and screening criteria must be defined uniquely
for each target and corresponding pharmacology. The model-based virtual
exploration of PK/PD relationships presented in this work offers one
approach to identify target pharmacology-specific PK drivers and the
associated potency-ADME space early in discovery to increase the probability
of success and, ultimately, clinical attrition.