Safety pharmacology is a branch of

pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...

specialising in detecting and investigating potential undesirable

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...

effects of new chemical entities (NCEs) on physiological functions in relation to exposure in the therapeutic range and above. Primary organ systems (so-called core battery systems) are: *

Central Nervous System The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

* Cardiovascular System *

Respiratory System The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...

Secondary organ systems of interest are: * Gastrointestinal System * Renal System 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.

Key aims of safety pharmacology

The aims of nonclinical safety pharmacology evaluations are three-fold: * To protect Phase I clinical trial volunteers from acute adverse effects of drugs * To protect patients (including patients participating in Phase II and III clinical trials) * To minimize risks of failure during drug development and post-marketing phases due to undesirable pharmacodynamic effects

Key issues

The following key issues have to be considered within safety pharmacology: * The detection of adverse effects liability (i.e. hazard identification) * Investigation of the mechanism of effect (risk assessment) * Calculating a projected safety margin * Implications for clinical safety monitoring * Mitigation strategies (risk management)

Background

The first appearance of the term ‘safety pharmacology’ in the published literature dates back to 1980. 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. 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 The is a cabinet level ministry of the Japanese government. It is commonly known as in Japan. The ministry provides services on health, labour and welfare. It was formed with the merger of the former Ministry of Health and Welfare or and the ...

. Nowadays, the term ‘general pharmacology’ is no longer used, and the ICH S7A guidelines 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. 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.

Preclinical safety pharmacology

Preclinical safety pharmacology integrates ''

in silico In biology and other experimental sciences, an ''in silico'' experiment is one performed on computer or via computer simulation. The phrase is pseudo-Latin for 'in silicon' (correct la, in silicio), referring to silicon in computer chips. It ...

'', ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

,'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' approaches. ''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 hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

)). Classically, ''in vivo'' investigations comprise the use of young adult conscious animals.

Study design

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.

Regulatory guidance documents (current versions)

The primary reference document for safety pharmacology is ICH S7A, followed by many key regulatory documents which either focus on or mention safety pharmacology: * ICH S7A: Safety pharmacology studies for human pharmaceuticals

* ICH S7B: Nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals

* ICH S6(R1): Preclinical safety evaluation of biotechnology-derived pharmaceuticals

* ICH S9: Nonclinical evaluation for anticancer pharmaceuticals

* ICH M3(R2): Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals

* ICH E14: Clinical evaluation of QT/QTc interval and proarrhythmic potential for non-antiarrhythmic drugs

* EMEA/CHMP/SWP/94227/2004. Adopted by CHMP. Guideline on the Non-Clinical Investigation of the Dependence Potential of Medicinal Products

* FDA U.S. Department of Health and Human Services Food and Drug Administration - Center for Drug Evaluation and Research (CDER). Guidance for Industry. Assessment of abuse potential of drugs. Final Guidance

* FDA U.S. Department of Health and Human Services Food and Drug Administration - Center for Drug Evaluation and Research (CDER). Guidance for Industry. Exploratory IND studies

References

External links

* http://cipaproject.org/
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