Drug selection in early drug development: screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches.

In the United States, only one in ten new chemical entities (NCEs) will successfully progress to the clinic. More than two-thirds of those that fail in development, other than for unacceptable efficacy, are the result of poor absorption, distribution, metabolism and excretion (ADME), and toxicology characteristics. In addition to supporting the appraisal of drug efficacy and safety during drug development, the role of ADME studies in supporting drug discovery efforts is increasing. However, since drug discovery and development have historically been treated as independent processes, the link between the two has been awkward. To complicate matters, recent advances in combinatorial chemistry and pharmacogenomics have increased the number of early drug candidates by several orders of magnitude, while development efforts remain expensive, low-throughput and time consuming. In order to make better promotion-to-development decisions and to handle the higher number of NCEs, the concept of drug selection has to become an integral part of the drug discovery/development paradigm. Drug selection is the process of characterizing drug candidates based on their ADME and toxicological properties and identifying candidates with the greatest potential to succeed in the clinic, while also filtering out potential development failures early in the process. The importance of drug selection is discussed and methods for selecting drugs based on their absorption properties are reviewed.