TY - JOUR T1 - EXTRAPOLATION OF PRECLINICAL PHARMACOKINETICS AND MOLECULAR FEATURE ANALYSIS OF “DISCOVERY-LIKE” MOLECULES TO PREDICT HUMAN PHARMACOKINETICS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1255 LP - 1265 DO - 10.1124/dmd.105.006619 VL - 34 IS - 7 AU - Evans, Christopher A. AU - Jolivette, Larry J. AU - Nagilla, Rakesh AU - Ward, Keith W. Y1 - 2006/07/01 UR - http://dmd.aspetjournals.org/content/34/7/1255.abstract N2 - The prediction of human pharmacokinetics from preclinical species is an integral component of drug discovery. Recent studies with a 103-compound dataset suggested that scaling from monkey pharmacokinetic data tended to be the most accurate method for predicting human clearance. Additionally, interrogation of the two-dimensional molecular properties of these molecules produced a set of associations which predict the likely extrapolative outcome (success or failure) of preclinical data to project human pharmacokinetics. However, a limitation of the previous analyses was the relative paucity of data for typical “discovery-like” molecules (molecular weight &gt;300 and/or clogP &gt;3). The objective of this investigation was to generate preclinical data required for extension of this dataset for additional discovery-like molecules and determine whether the aforementioned findings continue to apply for these molecules. In vivo nonrodent intravenous pharmacokinetic data were generated for 13 molecules, and data for 8 additional molecules were obtained from the literature. Additionally, the various scaling methodologies and molecular features analysis were applied to this new dataset to predict human pharmacokinetics. Whereas the predictive accuracies demonstrated across all of the various methodologies were lower for this higher clearance compound dataset, scaling from monkey liver blood flow continued to be an accurate methodology, and human volume of distribution was similarly well predicted regardless of scaling methodology. Lastly, application of the molecular feature associations, particularly data-dependent associations, afforded an improved predictivity compared with the liver blood flow scaling approaches, and provides insight into the extrapolation of high clearance compounds in the preclinical species to human. The American Society for Pharmacology and Experimental Therapeutics ER -