Principles of Safety Pharmacology

Matthew M. Abernathy, Abernathy, Matthew M.

Safety pharmacology satisfies a key requirement in the process of drug development. Safety pharmacology studies are required to assess the impact of a new chemical entity (NCE) or biotechnology-derived product for human use on vital systems, such as those subserving auditory function. Safety pharmacology studies accordingly are defined as those studies that investigate the potential undesirable effects of a substance on auditory functions in relation to exposure in and above the therapeutic range. Auditory safety studies should be designed with the primary objective of determining how administration of a compound influences normal hearing. If an effect on hearing is identified, then it is necessary to determine through histopathology the underlying mechanism for the observed hearing loss. Since the auditory system contains a heterogeneous mixture of structural and cellular components that are organized in a very complex and integrated manner, it is necessary to clearly identify the underlying primary mechanism or target of the new chemical entity that produced the hearing loss. This chapter will highlight major components of auditory function with regard to potential opportunities for drug interaction. Aspects of designing ototoxicity studies will be discussed with an emphasis on standards deemed necessary by the US Food and Drug Administration. Additionally, classes of ototoxic compounds and their proposed mechanisms of action are described in depth.