Secondary pharmacology studies are typically included in Investigational New Drug (IND) applications. They help to characterise the off-target activity risks of drug candidates, ideally, early in the drug discovery process from the lead generation stage and contribute to their safety evaluation. It is well established that activity at certain off-targets can be associated with adverse events (AEs) in humans, and that reducing target promiscuity may help limit the occurrence of drug related AEs (Brennan et al., 2024, ICH guideline S7A). However, despite the availability of extensive literature and public databases, understanding and predicting potential AEs linked to target modulation remains a significant challenge.
With the increasing number of targets requiring screening, computational approaches are becoming an attractive solution. In Vitro Safety Insight is a computational tool developed by Eurofins Discovery to support the interpretation of secondary pharmacology data from SafetyScreenTM panels, including the latest recommended targets (SafetyScreen77) from the leading pharmaceutical industries (Brennan et al., 2024).
The tool includes:
- A spatial overview and heatmap, focusing on the pharmacological data, enabling easier comparison between compounds and ranking.
- A custom hazard metric to assess organs at risk based on the compound’s pharmacological profile. This scoring system combines pharmacological data with target–adverse event associations derived from our database, which is built through a semi-automated process, integrating both public and proprietary sources.
- Suggested follow-up assays according to the organ system at risk to build a derisking strategy.
Figure 1 below: Secondary pharmacology data visualisation and interpretation figures displaying Organ System Hazard Metric Profile (OSHMP).
- A. Pharmacology data presented on a radar plot displaying inhibition percentage of the reference activity by the tested compounds (10 μM) on the target-based assays activity (binding and enzymatic). Target names in bold are those showing inhibition percentage higher than 50%, indicating a hit.
- B. Interpretation figures displayed as an OSHMP for tested SSRI compounds.
At Eurofins Discovery, we are committed to developing the most updated solutions for data-driven decision-making in support of human safety. For accurate risk assessment, the tool will be updated to a better version with more details on AEs related to each target and will require translational quantitative information (potency and plasmatic exposure) and contextualisation to refine interpretations and adapt risk mitigation strategies. For more information, visit: www.eurofinsdiscovery.com/solution/in-vitro-safety-insight
References:
1.Bowes, J., Brown, A. J., Hamon, J., Jarolimek, W., Sridhar, A., Waldron, G., & Whitebread, S. (2012). Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nature Reviews Drug Discovery, 11(12), 909–922. https://doi.org/10.1038/nrd3845
2. Brennan, R. J., Jenkinson, S., Brown, A., Delaunois, A., Dumotier, B., Pannirselvam, M., Rao, M., Ribeiro, L. R., Schmidt, F., Sibony, A., Timsit, Y., Sales, V. T., Armstrong, D., Lagrutta, A., Mittlestadt, S. W., Naven, R., Peri, R., Roberts, S., Vergis, J. M., & Valentin, J.-P. (2024). The state of the art in secondary pharmacology and its impact on the safety of new medicines. Nature Reviews Drug Discovery. https://doi.org/10.1038/s41573-024-00942-3
3. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. (2000). ICH S7A: Safety pharmacology studies for human pharmaceuticals. https://database.ich.org/sites/default/files/S7A_Guideline.pdf
4. https://emea.eurofinsdiscovery.com/solution/in-vitro-safety-insight