Page - (000091) - in Biomedical Chemistry: Current Trends and Developments

subgroups at potential risk to adjust dose regimens; Confirm dose/exposure response relationship in target population and subpopulations. in subgroups of target population; Determination of the pharmacokinetic profile of the final formulation of the drug candidate; Determination of a clear dose-response relationship in target population and subpopulations. Phase IV Dosage form improvements; Change drug formulation (modified release preparations, line extensions). Determination of the pharmacokinetic profile of new formulations; Determination of the pharmacokinetic profile of modified drugs designed to extend patent life; Determination of eventual influence of other drugs on the pharmacokinetic profile; ADME, absorption, distribution, metabolism and excretion; NCE, new chemical entity Independently of the precise nature of the screening technology, all methodologies must generally follow five criteria when designed and implemented during the discovery program (Fretland, 2010; Volpe, 2010): Table 2.1.2: Major in vitro model systems used to investigate the absorption, distribution and metabolism of new chemical entities in initial phases of drug discovery. In vitro model General characteristics Applications Absorption in vitro models PAMPA HTS assay rapidly performed in 96-well plates; Papp measurement through a hydrophobic filter impregnated with lipids; Compound quantification by UV/VIS spectrophotometry; Good predictability and easily to be automated. Screen NCEs in accordance to their absorption ability by transcellular passive diffusion; Prediction of human intestinal fraction absorbed. Caco-2 cell line Cells have human origin and encompass many characteristics of intestinal epithelium; Cells are grown on semi- Screen NCEs in accordance to their permeability through Caco-2 monolayer; Evaluation of absorption and prediction of human intestinal