The Need for Human Exposure Projection in the Interpretation of PreclinicalIn VitroandIn VivoADME Tox Data
Patrick Poulin · 2016
The field of toxicology is currently undergoing a global paradigm shift to use of in vitro approaches for assessing the risks of chemicals and drugs in a more mechanistic and high-throughput manner than current approaches relying primarily on in vivo testing. In particular, allometric and physiological modeling methods can be used to predict the in vivo exposure conditions that would produce chemical concentrations in plasma and/or the target tissue equivalent to the concentrations at which effects were observed with in vitro assays of tissue/organ toxicity. This chapter reviews the different modeling methods used for human pharmacoki-netic (PK) projection in drug discovery with an emphasis on the prediction of tissue distribution in toxicology studies. The influence of the compound selection process was examined by performing a probability analysis and examining the clearance (CL) properties of compounds that are selected using an idealized drug discovery screening process focused on PK optimization.