Seite - (000087) - in Biomedical Chemistry: Current Trends and Developments

high variable bioavailability and/or short half-life in animal studies were frequently prevented to progress to clinical trials. Furthermore, poor pharmacokinetic properties of new drug candidates in phase I clinical trials accounted for their clinical failure, while the incidence of severe (toxic) adverse side effects resulting from drug metabolism and drug-drug interactions (DDI) observed during phase II and III clinical trials may lead to the termination of potential new drugs or the withdrawal of marketed drugs. Although ADME studies are undeniably important throughout the stages of (non)-clinical drug development, some of the aforementioned failures could have been avoided if the pharmacokinetic deficits of the drug candidate were identified earlier in the discovery phase. The recognition that understanding the ADME processes of test compounds would potentially prevent their unsuccessful progression into clinical development phases expanded the ADME/pharmacokinetics interest from its traditional role as non- clinical safety support towards the early stage of drug discovery. Today, ADME/ pharmacokinetic studies are considered essential from drug discovery to phase IV clinical development and their main goals on each phase are summarized in Table 2.1.1. To attain these objectives, a range of in silico, in vitro and in vivo approaches have been developed and optimized as it will be further explained. 2.1.2.1 ADME/Pharmacokinetic Evaluation on Early Drug Discovery Phases As projects advance from the beginning of drug discovery (hit identification) to the last stage of drug discovery, which is named lead characterization and mostly performed in vivo, the required throughput (number of candidates to be considered) declines but assay predictability (content of information) increases proportionally. Most importantly, during the early and middle stages of drug discovery (including hit identification, lead identification and optimization), high- throughput screening (HTS) assays are utilized, allowing to test hundreds of compounds to be tested per day (Pereira, 2007; Carlson, 2008; Di, 2008; Wan, 2009). In current practice, even before NCEs are synthesized, in silico