Invited Review ArticleSafety pharmacology — Current and emerging concepts☆
Introduction
Non-clinical pharmacological studies, including primary pharmacology, secondary pharmacology and safety pharmacology (SP), are an essential element of the drug discovery and development process. Unlike primary and secondary pharmacology studies that explore the mode of action of the candidate drug and its effects related or unrelated to the therapeutic target, respectively, SP identifies the “potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above” (FDA, 2001) which are not identified by standard non-clinical toxicological studies. SP studies are, therefore, performed to ensure the safety of clinical participants in first in human (FiH) trials (Pugsley et al., 2008) through improved decision-making in the selection of lead candidate drugs. Efforts to standardize SP studies resulted in multiple guidelines from the International Conference on Harmonisation (ICH) including ICH S7A and S7B (FDA, 2001, FDA, 2005). The core battery SP studies, performed according to good laboratory practice (GLP) standards as per the ICH guidelines, involves the investigation of the major vital organ systems including the cardiovascular system (CVS), central nervous system (CNS) and respiratory system. In addition, supplemental studies investigating the renal and gastrointestinal (GI) systems and other organ specific follow-up investigations may compliment the core battery studies. However, these are optional and their conduct is determined by the nature of the lead candidate drugs being tested and the type of adverse events anticipated.
SP studies were generally performed during the drug development stage on the selected candidate drug prior to FiH trials. Currently, the onset of SP studies has shifted towards the early drug discovery process (Fig. 1). Thus, SP studies in addition to assessing and mitigating risks associated with the selected candidate drug can now facilitate lead candidate selection by hazard identification and elimination of new chemical entities (NCE) with safety liabilities (Valentin et al., 2009). The purpose of this review is to provide a combined and comprehensive overview of both current practices and newer technologies, followed by the emerging concepts in SP studies: frontloading, alternate models, integrated core battery assessments, integration of SP endpoints into regulatory toxicology studies, drug–drug interactions and translational SP.
Section snippets
Cardiovascular system
In the last few decades, a large number of drugs have been withdrawn from the market due to adverse cardiovascular system (CVS) effects, which were responsible for 45% of post-approval withdrawals (Laverty et al., 2011). The electrical activity in the CVS can be measured using electrocardiogram (ECG), which is analysed by dividing the recorded trace into waves and intervals with particular focus on the QT interval which represents cardiac repolarisation. It is important to note that QT
Gastrointestinal system
Gastrointestinal (GI) complications are common side effects, with varying degrees of severity, observed during and after drug development, and are associated with drug-induced morbidity (Pirmohamed et al., 2004). Drug induced GI complications include nausea, emesis, constipation and may also affect the absorption of other drugs. Therefore, it is important to study the effect of the test drug on the GI system (Harrison et al., 2004), routinely, to improve the safety and efficacy for NCE
Recent and emerging concepts
SP is continuously evolving and some recent trends to enhance and refine the scope include focus towards frontloading, exploration of alternate models, combining core battery tests, integration of SP endpoints into regulatory toxicology endpoints and correlation between non-clinical safety endpoints and clinical outcomes. As techniques and methodologies continue to improve, SP has adapted to contribute to improved decision making in lead candidate selection during drug discovery and development.
Summary
Over the last decade, SP has made tremendous progress in both the regulatory requirements and the knowledge gained while developing NCEs (Bass et al., 2011). A schematic summation of the current and emerging trends in SP studies is represented in Fig. 2. It has become increasingly evident that more suitable high throughput in vitro screening methods are required to be implemented at the earliest stages of drug discovery to obtain information about compounds prior to the initiation of clinical
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
We would like to thank Michael Hoffmann (Bayer Pharma, Germany), Brian Guth (Boehringer-Ingelheim, Germany), Andrea Parenti (Merck Serono Research, Merck KGaA, Germany), Herbert Himmel (Bayer Pharma, Germany), Julia Schlichtiger (Boehringer-Ingelheim, Germany), Christian Friechel (Roche, Switzerland) and Andrea Greiter-Wilke (Roche, Switzerland) for their input and guidance in the preparation of this manuscript. The financial contribution of the Innovative Medicines Initiative (IMI) SafeSciMET
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This review is an output by participants who attended an Innovative Medicines Initiative (IMI) SafeSciMET training programme on “Safety Pharmacology” (IMI SafeSciMET Course 4.6) conducted in 2012 at the MRC Centre for Drug Safety Science, University of Liverpool, UK.
- 1
SafeSciMET: European Modular Education and Training Programme in Safety Sciences for Medicines (www.safescimet.eu).
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Equal contributors.