Safety Pharmacology Society Annual Meeting

Until now, there were only a very few receptors (notably hERG; NaV1.5; ENT1) with a well-defined, evidence-based safety margin between in vitro potency and in vivo clinical exposure to enable quantitative off-target safety risk assessment of a novel compound. We have addressed this gap through the development of Secondary Intelligence™, an expert-curated knowledge base, coupled with a novel software platform for data visualisation and report generation. The current version supports analysis of compound interactions at the 44 receptors recommended by Bowes et al. (2012) to provide an assessment of potential hazards due to off-target activity. We are adding to this with additional panels of receptors. The user uploads screening data from Excel and the software performs a comparison with reference drugs selective for a particular receptor, based upon the calculated receptor occupancy. We kept this simple: if the calculated receptor occupancy of your test compound is comparable to the reference drugs, it is flagged as having a high likelihood of interacting with that receptor in clinical use. If it has a lower occupancy within one log unit of the reference drugs, it is assigned a ‘medium’ rating. And if the occupancy is less than one log unit lower than the reference drugs, it is assigned a ‘low likelihood’ of interacting with the receptor in clinical use. In addition, Secondary Intelligence allows you to run ‘What if?’ scenarios, e.g., to model situations which may change the unbound Cmax value of your test compound. It also contains useful information including lists of drugs and research compounds targeting each receptor, safety pharmacology outcomes and clinical side effects associated with the receptor, together with translatable biomarkers when available. It also contains Mechanistic Safety Pathways. These illustrate in a standardised format how a particular pharmacodynamic effect is brought about by a drug interacting with that receptor, supported by key references. Plus, you can autogenerate an editable report in Word by a single click. In this webinar, Will Redfern PhD (Vice President, Quantitative Systems Toxicology & Safety, Certara) will present on the software in more detail, including case studies involving off-target hits.