Exploratory Safety Pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations

Abstract

The primary objective of Safety Pharmacology is to ensure the safety of medicines on physiological functions in order to protect humans against adverse drug reactions. Safety Pharmacology became a major non-clinical discipline in 2000 when the International Conference on Harmonization approved the S7A guideline. This regulatory document requires pharmaceutical companies to undertake Safety Pharmacology assessment under Good Laboratory Practice (GLP) in order to guarantee the absence of unmanageable risks on vital organ function for compounds to be tested on humans. These regulatory studies often reveal liabilities impacting on the smooth transition of drug candidates from the discovery phase into the clinical arena. However, if these safety issues were uncovered prior to regulatory science assessment, the chemistry of poorly safe molecules could be modified during the lead optimisation phase for preventing later occurring attrition accidents. This article proposes the establishment of a spin-off specialty of Regulatory Safety Pharmacology, for which the name ‘Exploratory Safety Pharmacology’ is proposed. The objective of this discipline would be to conduct early safety investigations on potential drug candidates by applying, outside the constraints of GLP, in silico, in vitro, ex vivo and in vivo platforms translating clinical liabilities into simple, fast and cost-effective screening assays. This approach should result in early hazard detection with rapid turnaround of the data, enabling medicinal chemists to mitigate the safety liabilities of new compounds in an iterative manner. Hence, the ultimate aim of Exploratory Safety Pharmacology activities is to transform Regulatory Safety Pharmacology investigations into risk-known exercises.

Keywords::

• assay validation
• cardiovascular system
• CNS
• drug development
• exploratory non-clinical development sciences
• Exploratory Safety Pharmacology
• in silico investigations
• pathways analysis
• Regulatory Safety Pharmacology
• respiratory system
• risk detection and assessment
• strategy to reduce non-clinical attrition
• S7A and S7B guidelines
• vital organ safety assessment

Acknowledgements

The author thanks A Al-Saffar, J-C Blanchard, K Bruse, H Kaplan, D Gallagher, F Gannier, T Guia, M-C Guillet, J-M Guillon, L Kinter, J Lavayre, J Llenas, I MacKenzie, D Murphy, S Pestel, W Redfern, A Roach, R Towart, H Vargas and P Zitoun for reviewing the full or selected parts of this contribution.

The author assumes full responsibility for the content of the report.