PK/PD at a cellular level to avoid misinterpretation

Quantitative Imaging for Rapid Target Exposure and Drug Efficacy Assays by Martin PAINE, PhD


Drug efficacy is irrelevant if it can’t reach the intended biological target. Based on in vitro efficacy results, drug candidates may proceed deep into the clinical phases only to realize afterwards the in vivo efficacy is poor. A major reason for this is the inability for drugs to reach their intended target in the required concentrations; for example, the ability of a drug to cross the blood-brain barrier (BBB). Obtaining target exposure information earlier in the development process translates directly to time and cost savings in the clinical phases. To achieve this, histological distributions of drugs and related metabolites (exogenous and endogenous) must be visualized with absolute quantitation, and their co-localization with the biological target measured.

In this webinar, we present a new way to visualize and quantify drugs, enzyme activity, and biomarkers at the cellular level by combining our patented quantitative mass spectrometry imaging (QMSI) methodology with our latest Multimaging software developments. The method is label-free and translational from pre-clinical through to clinical phase samples. Using this method, we investigated the target exposure of tumors treated with epacadostat and its efficacy on the IDO1 enzyme by quantifying the changes in tryptophan and kynurenine. We were able to link the topographic and molecular localization of the drug and metabolites (QMSI) with the biological target (immunostaining).

This result confirmed that more than just reaching the organ of interest, the drug also reached its specific enzymatic molecular target by calculating the percentage of drug target exposure based on the spatial correlation as well as a percentage of target engagement based on the enzyme product/substrate ratio. As exposure at the site of action and to its specific target were identified as the most important factors for success in drug discovery and the design of chemical probes, these results showed and confirmed the high contribution of MSI to provide simultaneous readouts of on-target and off-target activity.


March 7

8:00 am, Pacific Standard Time (San Francisco, GMT-08:00)
11:00 am, Eastern Standard Time (New York, GMT-05:00)
5:00 pm, Europe Time (Paris, GMT+01:00)
4:00 pm, GMT Time (London, GMT)

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