Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Abstract

The inclusion of pharmacological studies (also known as general, secondary, or ancillary pharmacology) in the safety evaluation of new drugs is a well-established practice (Zbinden 1966; Alder and Zbinden 1973). These studies contribute to the safety profile of potential new drugs and provide pharmacological data that can be used for optimization of further compounds and the ultimate selection of compounds suitable for clinical development. The emergence of safety pharmacology as a specialty area distinct from toxicology was facilitated by the appearance of the ICH S7A guideline in which the rationale for safety pharmacology studies was laid out, and study types were defined (The European Agency for the Evaluation of Medicinal Products. Human Medicine Evaluation Unit 2000). However, one topic in particular was instrumental in focusing attention on safety pharmacology studies, namely the concern about drugs causing severe ventricular arrhythmias, including torsades de pointes and, in some cases, sudden death. One must not forget, however, that the purpose of conducting cardiovascular safety pharmacology studies is not just to define a specific proarrhythmic risk but to examine potential effects on the peripheral vasculature, the heart, or any other effect that may secondarily lead to an activation or depression of cardiovascular performance (Sarazan et al. 2011).