Quantifying the probability of pharmacological success to inform compound progression decisions

The Probability of Pharmacology Success, or PoPS, is a powerful metric to inform progression decisions by quantifying a compound's overall pharmacological strength based on its mechanism. It is defined as the probability that X level of pharmacology is achieved in Y proportion of patients at a safe dose. The importance of adequate drug exposure, target engagement and functional pharmacology for enabling a compound's efficacy is widely recognized. The PoPS estimates how well these conditions are met by integrating the compound's pharmacological properties and the target's modulation needs for the intended indication, in a pharmacometric model that includes the knowledge uncertainty. We use examples to illustrate how it can be used to compare drug candidates under specified benefit and risk conditions, support first-in-human decisions based on exposure limits, advise preclinical lead optimisation, and define clinical-trial populations.