Safety and Drug Metabolism: Toward NCE and First in Human

The attrition rate of new chemical entities (NCEs) for central nervous system (CNS) drugs is relatively high, making the development of new CNS drugs a challenge. A significant cause are safety issues arising either during animal toxicity testing or in the human clinical test phases. Assessing the potential adverse effects of CNS pharmaceuticals more precisely and efficiently is done by the development of assessment frameworks that include new approach methodologies (NAMs). NAMs integrate 1) (novel) cell (2D/3D) and tissue methods (in vitro); 2) structure-based/toxicokinetic models (in silico); 3) methods that assess toxicant interactions; with 4) biological macromolecules (in chemico); and 5) alternative (animal) models. These NAMs are expected to improve the safety testing strategy of NCEs and to increase approval rates by regulatory agencies of potential candidate drugs. This will prevent safety issues when potential new drugs are first applied in humans and lead to a better understanding of the biological mechanisms involved. It also will provide support to an earlier discovery of additional adverse health effects of existing and newly developed CNS drugs so that attrition rates in the clinical test phases will be lowered.