Safety pharmacology is a branch of pharmacology specialising in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities (NCEs) on physiological functions in relation to exposure in the therapeutic range and above.[1]
Primary organ systems (so-called core battery systems) are:
Secondary organ systems of interest are:
Safety pharmacology studies are required to be completed prior to human exposure (i.e., Phase I clinical trials), and regulatory guidance is provided in ICH S7A and other documents.[2][3]
The aims of nonclinical safety pharmacology evaluations are three-fold:
The following key issues have to be considered within safety pharmacology:[4]
The first appearance of the term ‘safety pharmacology’ in the published literature dates back to 1980.[5] The term was certainly in common usage in the 1980s within the pharmaceutical industry to describe nonclinical pharmacological evaluation of unintended effects of candidate drugs for regulatory submissions.[6] Back then, it was part of a wider ‘general pharmacology’ assessment, which addressed actions of a drug candidate beyond the therapeutically intended effects. The only detailed guidelines indicating the requirements from drug regulatory authorities for general pharmacology studies were from the Ministry of Health, Labour, and Welfare. Nowadays, the term ‘general pharmacology’ is no longer used, and the ICH S7A guidelines[7] distinguish between primary pharmacodynamics (“studies on the mode of action and/or effects of a substance in relation to its desired therapeutic target”), secondary pharmacodynamics (“studies on the mode of action and/or effects of a substance not related to its desired therapeutic target”) and safety pharmacology (“studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.”). A major stimulus to the discipline of safety pharmacology was the release in 1996 of a draft ‘Points to Consider’ document on QT prolongation by the European Medicines Agency's Committee for Proprietary Medicinal Products (CPMP), issued in final form the following year.[8] This initiative had been prompted by growing concern of sudden death caused by drug-induced torsade de pointes, a potentially lethal cardiac tachyarrhythmia. Later, in 2005, this concern was addressed by issue of the ICH S7B guidelines.[9]
Preclinical safety pharmacology integrates in silico, in vitro, and in vivo approaches.[10] In vitro safety pharmacology studies are focused on early hazard identification and subsequent compound profiling in order to guide preclinical in vivo safety and toxicity studies. Early compound profiling can flag for receptor-, enzyme-, transporter-, and ion channel-related liabilities of NCEs (e.g., inhibition of the human ether-a-go-go related gene protein (hERG)). Classically, in vivo investigations comprise the use of young adult conscious animals.
Safety pharmacology studies have to be designed for defining the dose-response relationship of the adverse effect observed. Justification should be provided for the selection of the particular animal model or test system. The time course (e.g., onset and duration of response) of the adverse effect is investigated through selected time points for the measurements based on pharmacodynamic and pharmacokinetic considerations. Generally, the doses eliciting the adverse effect have to be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans.
The primary reference document for safety pharmacology is ICH S7A, followed by many key regulatory documents which either focus on or mention safety pharmacology: