Principles of Safety Pharmacology

Gary Gintant, Gintant, Gary

In vitro screening for cardiovascular safety liabilities of novel drug candidates presents a challenge for the pharmaceutical industry. Such approaches rely on detecting pharmacologic effects on key components of complex integrated system early in drug discovery to define potential safety liabilities. Key to such studies are the concepts of hazard identification vs. risk assessment, drug specificity vs. selectivity, and an appreciation of the challenges faced when attempting to translate in vitro findings to preclinical in vivo as well as clinical effects. This chapter defines some key aspects of early safety pharmacology screening for cardiovascular liabilities, citing studies of two key depolarizing cardiac currents (fast sodium current and L-type calcium current) as examples linked to effects on cardiac conduction and repolarization.