Pharmacodynamics studies the effect of a drug or drug candidate in an in vivo setting. There is a key difference between a pharmacodynamic readout and an efficacy readout. The former is typically a molecular event taking place in the close proximity of the target of a therapeutic intervention, whereas the latter is a later event, in most cases relying on clinical phenotypic measures.
Therefore, the development and validation of a pharmacodynamic assay should be initiated even at an in vitro stage, very early in the process of supporting drug discovery efforts.
Pharmacodynamic assays typically stem from, or sometime overlap with, target engagement assays. In fact, it is it very relevant for a pharmacodynamic readout to be the earliest possible readout in the chain of events triggered by the therapeutic entity so that:
- A measure of the reach of target tissue by active molecules is obtained
- A determination of the minimal efficacious modulation of the target can be estimated
- The ranking of compounds with different pharmacokinetics is improved
The ultimate goal is to establish a pharmacokinetics/pharmacodynamics correlation, where the right dosage required to generate a meaningful biological event at the target tissue is determined, eventually producing a therapeutic effect.
We adopt multiple approaches, both in vivo and ex vivo, including:
- Transcriptional profiling (e.g. on PBMCs or other blood cells)
- Signaling pathway measures (e.g. ex vivo via immunoassays)
- Target protein levels in relevant biofluids (e.g. detection of CNS gene therapy target proteins in animal and human CSF).
- In-life measures with luciferase reporter
The setup of a pharmacodynamic assay is must take into account the features of in vivo and ex vivo techniques. The former are clearly less invasive, but often requires molecular modifications that are not suitable for clinical studies. The latter must consider that the processing required to carry out the readout might heavily influence the outcome.
To mitigate these issues and produce the right tools for pharmacodynamic readout of each project, we always ensure that more than one strategy is considered. Furthermore, we carry out a thorough validation to gain the best confidence in the readout.
