Time‐evolved metrics for safety pharmacological assessments of small molecules and biologics

Abstract Safety of a small‐molecule drug is oftentimes a more important criterion than efficacy in determining drug approval. Aspects of safety pharmacological and toxicological liabilities, often resulting from dose‐dependent undesirable interaction with either the primary target of interest or secondary targets, have a huge role to play in determining ‘first‐in‐human’ dosage and phase I clinical trials. Given the open thermodynamic nature of the human subjects, it is mandatory that kinetics of drug‐target and drug‐off‐target interactions govern the way selectivity margins are assessed, and dose is decided. However, lack of sufficient thrust on kinetics in guiding early drug discovery decisions has resulted in an overreliance on IC 50 measure (a proxy for thermodynamic K i ) as a means of computing safety across the target of interest and potential off‐targets. Moreover, based on established practises and known weight of evidence of targets with safety adverse events, the primary panel of secondary pharmacology targets are biased with greater preference for G‐protein coupled receptors, transporters and ion‐channels with a paucity of enzymes. This can pose unique challenges in assessing safety, especially for advancing and emergent modalities. In this perspective, the critical role kinetic margins should play in assessing safety is emphasised given the myriad assay conditions that can modulate the equilibrium thermodynamic measure as embodied in the proxy report of IC 50 . Further, it advocates selective and judicious expansion of primary safety panels with greater representation of enzymes and reduced redundancy in eventual read‐outs based on potential for correlative output among the off‐target classes assessed.