Fractional mass filtering as a means to assess circulating metabolites in early human clinical studies

摘要: Recent changes in the regulatory environment have led to a need for new methods assess circulating human drug metabolites early clinical studies with respect their potential toxicological impact. The specific goals of such are determine if present plasma following administration candidate also observed from animal employed preclinical evaluation, and estimate corresponding exposure margins (animal:human) major metabolites. Until recently, accepted best practice characterization utilized liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based methodologies, conjunction authentic chemical standards, detection quantitative analyses predicted both experiments liver preparations vitro. While this approach is satisfactory anticipated biotransformation products, that were not expected circulate frequently escape detection. Current accurate instruments enable use technique fractional filtering detect unexpected rapid, less resource-intensive more robust manner. Application technology several development programs at Merck Research Laboratories has demonstrated value assessment trials.