Recalibration of nonclinical safety pharmacology assessment to anticipate evolving regulatory expectations

Abstract

Safety pharmacology (SP) has evolved in terms of architecture and content since the inception of the SP Society (SPS). SP was initially focused on the issue of drug-induced QT prolongation, but has now become a broad spectrum discipline with expanding expectations for evaluation of drug adverse effect liability in all organ systems, not merely the narrow consideration of torsades de pointes (TdP) liability testing. An important part of the evolution of SP has been the elaboration of architecture for interrogation of non-clinical models in terms of model development, model validation and model implementation. While SP has been defined by mandatory cardiovascular, central nervous system (CNS) and respiratory system studies ever since the core battery was elaborated, it also involves evaluation of drug effects on other physiological systems. The current state of SP evolution is the incorporation of emerging new technologies in a wide range of non-clinical drug safety testing models. This will refine the SP process, while potentially expanding the core battery. The continued refinement of automated technologies (e.g., automated patch clamp systems) is enhancing the scope for detection of adverse effect liability (i.e., for more than just IKr blockade), while introducing a potential for speed and accuracy in cardiovascular and CNS SP by providing rapid, high throughput ion channel screening methods for implementation in early drug development. A variety of CNS liability assays, which exploit isolated brain tissue, and in vitro electrophysiological techniques, have provided an additional level of complimentary preclinical safety screens aimed at establishing the seizurogenic potential and risk for memory dysfunction of new chemical entities (NCEs). As with previous editorials that preface the annual themed issue on SP methods published in the Journal of Pharmacological and Toxicological Methods (JPTM), we highlight here the content derived from the most recent (2015) SPS meeting held in Prague, Czech Republic. This issue of JPTM continues the tradition of providing a publication summary of articles primarily presented at the SPS meeting with direct bearing on the discipline of SP. Novel method development and refinement in all areas of the discipline are reflected in the content.