Safety pharmacology
Safety pharmacology is a branch of
Primary organ systems (so-called core battery systems) are:
- Central Nervous System
- Cardiovascular System
- Respiratory System
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.[2][3]
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:[4]
- 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
Background
The first appearance of the term ‘safety pharmacology’ in the published literature dates back to 1980.
Preclinical safety pharmacology
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.
Study design
Safety pharmacology studies have to be designed for defining the
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. [1].
- ICH S7B: Nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. [2].
- ICH S6(R1): Preclinical safety evaluation of biotechnology-derived pharmaceuticals. [3].
- ICH S9: Nonclinical evaluation for anticancer pharmaceuticals. [4].
- ICH M3(R2): Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. [5].
- ICH E14: Clinical evaluation of QT/QTc interval and proarrhythmic potential for non-antiarrhythmic drugs. [6].
- EMEA/CHMP/SWP/94227/2004. Adopted by CHMP. Guideline on the Non-Clinical Investigation of the Dependence Potential of Medicinal Products. [7].
- 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. [8].
- 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. [9].
See also
- SPS: There is a global scientific society fostering best practice within the discipline of safety pharmacology. This Safety Pharmacology Society (SPS) promotes knowledge, development, application, and training in safety pharmacology.
- CiPA: Comprehensive in vitro Proarrhythmia Assay (2013)[10]: In the coming years, the FDA plans to update the current regulatory documents for preclinical and clinical safety evaluation of proarrhythmic risk in human (i.e. ICH-S7B and ICH-E14). The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety pharmacology paradigm intending to provide a more accurate assessment of cardiac safety testing for potential proarrhythmic events in human.[11] This initiative is driven by a steering team including partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The CiPA includes in vitro assays coupled to in silico reconstructions of cellular cardiac electrophysiological activity with verification of relevance through comparison of drug effects in human stem cell-derived cardiomyocytes. If these evaluation efforts succeed, CiPA will become a Safety Pharmacology screening tool for drug research and development purposes.[12] The CiPA Steering Committee and the ICH-S7B and ICH-E14 Working Groups will position the CiPA paradigm within the upcoming revisions of the a forementioned regulatory documents.[13]
References
- PMID 15172010.
- ^ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
- ^ "ICH Official web site : ICH".
- PMID 18604233.
- PMID 7194053.
- ^ Redfern WS, Wakefield, ID (2006) Safety Pharmacology. In Toxicological Testing Handbook: Principles, Applications and Data Interpretation, 2nd edn., pp. 33-78. K Keller & D Jacobson-Kram (eds.), Taylor & Francis Ltd.
- ^ EMA ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals. ICH Step 5: Note for Guidance on Safety Pharmacology Studies for Human Pharmaceuticals. CPMP/ICH/539/00.
- ^ Redfern WS, Wakefield ID, Prior H, Pollard, CE, Hammond TG, Valentin J-P. (2002) Safety pharmacology – a progressive approach. Fund Clin Pharmacol 16, 161-173.
- ^ "ICH Official web site : ICH".
- ^ Handbook of Experimental Pharmacology. Principles of Safety Pharmacology. Editors: Pugsley, Michael K., Curtis, Michael J. (Eds.), 2015.
- PMID 24576511.
- ^ Authier S, Pugsley MK, Koerner JE, Fermini B, Redfern WS, Valentin JP, Vargas HM, Leishman DJ, Correll K, Curtis MJ. Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice. J Pharmacol Toxicol Methods. 2017 Feb 20;86:34-43.
- S2CID 33369081.
External links
- http://cipaproject.org/
- emka TECHNOLOGIES Physiological data acquisition & analysis for preclinical research