The failure of in vitro ADME properties to correctly determine in vivo outcomes

COMP 194

Daniel A. Norris, Troy Bremer, Kevin Holme, Glen Leesman, and Manish Sud. LION bioscience Inc, 9880 Campus Point Drive, San Diego, CA 92121
In vitro ADME properties have long been used as surrogates for in vivo pharmacokinetic outcomes to compare drugs and drug candidates. Some properties, such as Caco-2 permeability and metabolic turnover are widely used in high throughput assays to select hits, leads, and candidates early in the drug discovery process. The value of these properties to provide accurate information for drug selection decisions has been investigated. Clinical pharmacokinetic data, in vitro ADME assay data and chemical structure data were assembled for > 150 compounds. The ability of each in vitro assay (used individually, jointly, or in simple correlation models) to predict in vitro outcomes was determined. In each case, the in vitro ADME properties were unable to provide accurate information regarding the pharmacokinetic performance of the compounds. The failure of these assays to determine pharmacokinetic outcomes should be considered when making drug discovery decisions based on this type of data.