Does in vitro potency predict clinical efficacious concentrations

The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n=164) and how they may differ depending on therapeutic indication, mode-of-action, receptor type, target localisation and function. Approximately 70 % of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median Ratio of exposure in relation to in vitro potency was 0.32, and 80% had Ratios within 0.007 and 8.7. We identified differences in the in vivo-to-in vitro potency Ratio between indications, mode-of-action, target type and matrix localisation, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest, within the same drug target and mode of action the within-variability was slightly broader, but both were substantially less compared to the overall distribution of Ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.