Principles of Safety Pharmacology

Abstract

Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.).

Measurement of respiratory function using whole-body plethysmography in unanesthetized and unrestrained nonhuman primates

“…-22 - present study showed relatively large variability, which phenomenon has been also reported in unanesthetized, unrestrained rats (Pugsley et al, 2008), so it may be said that the values of respiratory parameters show relatively greater variation under the conditions of non-anesthetization and free mobility, regardless of animal species.…”

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

“…To date, no studies on the effects of a dopamine D 3 receptor antagonist and cocaine in dogs have appeared. Dogs are a mainstay of cardiovascular safety evaluation of drugs (Pugsley et al, 2008;Ewart et al, 2013). Although it is uncertain whether the interaction between a dopamine D 3 receptor antagonist and cocaine we are reporting in dogs is predictive of a similar effect in humans, this finding would likely preclude further development of such a compound as a treatment for cocaine use disorder.…”

Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

“…Exposure of these cultured neurons to a drug candidate can determine at an early stage of preclinical testing whether the drug is toxic to neurons and, for example, initiates apoptosis ). An important aim in drug development is to discover detrimental effects as early as possible (Pugsley et al, 2008). This is of particular importance when testing new antiepileptic drugs that interfere with glutamate (as NMDA antagonists) or GABA signaling, or to discover off-target effects of other potential drugs.…”

“…Lack of safety contributes to 30% of failures, whereas lack of efficacy is the other major cause of attrition (Kola and Landis, 2004). The fact that several drug candidates progressed well into clinical trials before rare and potentially lethal adverse effects were detected led to an extension of nonclinical trials and the foundation of safety pharmacology as a discipline in the late 1990s (Pugsley et al, 2008). One of the ICH M3 (R2) safety guidelines referenced is S7A, "Safety Pharmacology Studies for Human Pharmaceuticals," (ICH, 2009) which defines a core battery of vital organs for which the impact of new drugs needs to be assessed.…”

“…However, animal models phylogenetically closer to mammals with well characterized CNS, cardiovascular, and respiratory systems are needed to better predict alteration in organ function relevant for humans. Established animal models in safety pharmacology may include pigs, monkeys, primates, and dogs, models that require substantial care and tend to stir public opinion (Pugsley et al, 2008). It would therefore be advantageous to develop additional models that, in the early exploratory phase, could help reduce the number of drug leads that later need to be tested in the established animal models.…”