Genotoxicity assessment of drug metabolites in the context of MIST and beyond

While dedicated guidelines for industry exist regarding the assessment of the genotoxic potential of new pharmaceuticals and impurities, and the general safety assessment of major drug metabolites, only limited guidance exists on the assessment of potential genotoxic minor drug metabolites. In this perspective paper, we discuss challenges associated with assessing the genotoxic potential of human metabolites and share five case studies within the context of an 'aware-avoid-assess' paradigm. A special focus is on a class of potentially genotoxic carcinogens: aromatic amines (arylamines, anilines). This compound class is frequently used as building blocks and may show up as impurities, metabolites or degradants in pharmaceuticals. We propose several recommendations that should help project teams at different stages of pharmaceutical development. In most cases, proactive interactions with the relevant health authority should be considered in order to endorse the proposed genotoxicity assessment strategy for ...