Currently,a variety of high-throughput based physicochemical screening and DMPK assays is being widely applied in drug discovery to search for drug-like candidates towards different new targets.At an early phase of drug discovery projects,the evaluation of lead series and potential compound selection for further in vivo tests are primarily based on multiple in vitro data but very limited in vivo data.Thus,a reasonably good in vitro in vivo correlation is essential for compound selection and decision-making.Without a proven in vitro in vivo correlation,some potential drug-like compounds might be discarded or never tested in vivo.Likewise,some undesired compounds could be unnecessarily tested in vivo,leading to an increased workload,screening costs and waste of animals life.In this talk,we will give a retrospective overview on current physicochemical screening and ADME profiling regarding in vitro in vivo correlations.We will address the importance of physicochemical properties and ADME parameters for compound selection and compound design by an integrated approach.General strategies for human clearance predictions will be exemplified using the well-stirred hepatic liver model and single animal species in vivo PK approach to support early drug discovery projects.In particular,we will compare the impact of input parameters on hepatic clearance prediction performance in different models,e.g.the optimal model (with all experimentally determined values as input parameters in the well-stirred model) versus simplified models (with incomplete input parameters or equations).The differences between in vitro potency relative to in vivo effect and various targets (typically agonists versus antagonists) will be demonstrated,which highlights the necessity of frontloading PK/PD for the target validation and decision-making at early stages in addition to good in vitro in vivo correlations.