Developing Robust Human Liver Microsomal Stability Prediction Models: Leveraging Inter-Species Correlation with Rat Data

Pharmacokinetic issues were the leading cause of drug attrition, accounting for approximately 40% of all cases before the turn of the century. To this end, several high-throughput in vitro assays like microsomal stability have been developed to evaluate the pharmacokinetic profiles of compounds in the early stages of drug discovery. At NCATS, a single-point rat liver microsomal (RLM) stability assay is used as a Tier I assay, while human liver microsomal (HLM) stability is employed as a Tier II assay. We experimentally screened and collected data on over 30,000 compounds for RLM stability and over 7000 compounds for HLM stability. Although HLM stability screening provides valuable insights, the increasing number of hits generated, along with the time- and resource-intensive nature of the assay, highlights the need for alternative strategies. One promising approach is leveraging in silico models trained on these experimental datasets.