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Safety Pharmacology
Safety Pharmacology SS Anand, DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE, USA BK Philip, Bristol-Myers Squibb, Mount Vernon, IN, USA HM Mehendale, University of Louisiana at Monroe, Monroe, LA, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by S. Satheesh Anand and Harihara M. Mehendale, volume 3, pp 754–759, Ó 2005, Elsevier Inc.
Definition of Safety Pharmacology Safety pharmacology is defined as the subdivision of pharmacology that investigates the potentially undesirable pharmacodynamic effects on physiological functions in relation to exposure in the therapeutic range and above in determining whether and how (dose regime, subject selection) a new drug can be administered safely to human subjects.
Background Successful drug development requires precise drug safety assessment. The importance of evaluating the safety of medicinal products before they are allowed on the market was realized following unacceptable levels of unanticipated deaths occurring after drugs have entered the market. The eventual regulatory requirements were reached at different times in different regions. A tragic mistake in the formulation of a children’s syrup in the 1930s in the United States and the thalidomide tragedy in the 1960s in Europe are some examples that triggered the regulations requiring product authorization. Traditionally, drug safety studies are designed to examine effects other than the primary therapeutic effect of a drug candidate. While these studies evaluate the toxic profile of the drug candidate at maximum tolerated dose and in selected organs, the effects on normal physiological functions at therapeutic doses have long been neglected. Deaths and adverse effects of drugs have been reported in patients and clinical trial participants due to failure in physiologic functions. Pharmacoepidemiology studies in Europe and the United States have shown that adverse drug reaction accounts for up to 10% of admissions in hospitals. In the United States, from 1954 until 1980, 7 million people participated in clinical trials. Safety pharmacology studies are developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources. Until recently, there have been no internationally accepted definitions, objectives, or recommendations on the design and conduct of safety pharmacology studies. The harmonization in regulation was impelled by concerns over rising costs of health care, escalation of the cost of research and development, and the need to meet the public expectation that there should be a minimum of delay in making safe and efficacious new treatments available to patients in need. In 1990, representatives of the regulatory agencies and industry associations of Europe, Japan, and the United States proposed the International Conference on Harmonization (ICH) to develop harmonized guidance on technical issues aimed at ensuring that good-quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest
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of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans, and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. The ICH guideline on safety pharmacology (ICH S7A) was recommended for adoption by regulatory bodies in the European Union, United States, and Japan in November 2000, and it has been in effect worldwide since 2001. With this guideline calling for tests on the effects of compounds on vital functions of the human body, the data providing specific information on the safety profile of a new potential therapeutic agent used by clinicians designing clinical studies and by regulatory agencies in their assessment of the safety of a new product are crucial. A brief description of the safety pharmacology studies is presented in this article. Genetic profiling early in a drug0 s development to study variations in pharmacokinetic and pharmacodynamic profiles would help correlate genetic biomarkers with drug response. Pharmacogenomics and pharmacokinetics together with progress in genetic biotechnology are starting to change the approach to drug discovery for the treatment of complex diseases. Thus, it can be affirmatively predicted that efficiency in drug development, and safety and efficacy in drug administration, can be gained from coordinated collection of pharmacogenetic data. The transparency, quality, and completeness of genetic data collected from patients will determine the pace at which new drugs will be discovered and brought safely to market. Efforts and close coordination between the US Food and Drug Administration (FDA), research institutes, clinicians, and pharmaceutical companies are already optimal. Pending legislation in the US Congress holds great potential to facilitate a faster and more transparent approval process for new drugs, while providing improved corresponding diagnostic tests. The Role of Safety Pharmacology in a Regulatory Agency (FDA)*
Safety pharmacology studies, which investigate potential undesirable pharmacodynamic effects of a test substance on physiological function in relation to exposure, play an important role in determining whether and how (dose regime, subject selection) a novel test substance can be administered safely to human subjects. Core studies on key systems (central nervous, respiratory, and cardiovascular systems) constitute an important component of the initial safety evaluation, and are reviewed prior to the first administration to human studies. Hazard identification and risk evaluation are key aspects of the evaluation, and can be critical in the design of clinical trials.
Encyclopedia of Toxicology, Volume 4
http://dx.doi.org/10.1016/B978-0-12-386454-3.00352-3
Safety Pharmacology
Pharmacologist/toxicologists are tasked with reviewing safety pharmacology studies, and interact with other members of the review team, which include medical officers, clinical pharmacologists, chemists and project managers. Pharmacologists/ toxicologists also interact with industry scientists to evaluate specific concerns related to mechanism of action and empirical findings seen in other studies or with similar test substances. Source: Safety Pharmacology Society http://www.safetypharmacology.org/ whatisSP.asp.
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be transiently disrupted by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate investigative concern. Safety pharmacology evaluation of effects on these other systems may be of particular importance when considering factors such as the likely clinical trial or patient population, for example, gastrointestinal tract in Crohn’s disease, renal function in primary renal hypertension, and immune system in immunocompromised patients. The safety pharmacology studies should be conducted in compliance with good laboratory practice (GLP). When the studies are not conducted in compliance with GLP, data quality and integrity should be ensured. These safety pharmacology end points can also be obtained from adequately designed and conducted GLP toxicology studies, thereby eliminating the need for separate safety pharmacology studies.
Types of Pharmacological Studies Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies. Studies on the mode of action or effects of a substance in relation to its desired therapeutic target are primary pharmacodynamic studies. Studies on the mode of action or effects of a substance not related to its desired therapeutic target are secondary pharmacodynamic studies. These have sometimes been referred to as part of general pharmacology studies. Safety pharmacology studies critically assess unanticipated effects of new drug candidates on major organ functions at exposures in the therapeutic range and above. Organ systems evaluated primarily are cardiovascular, respiratory, and central nervous systems. The supplemental evaluations are renal/urinary function, gastrointestinal function, and immune function assessment. In addition to these batteries of tests, knowledge of potential harmful interactions or interactions between medications that may neutralize the beneficial effects is becoming increasingly important to evaluate the coadministration of drugs.
Objectives of Safety Pharmacology Studies The objectives of safety pharmacology studies are (1) to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety; (2) to evaluate adverse pharmacodynamic or pathophysiological effects of a substance observed in toxicology or clinical studies; and (3) to investigate the mechanism of the adverse pharmacodynamic effects observed or suspected. The methods used must be validated, well established, should be in common use, and should give reliable, reproducible results every time. The study design should consider the available in vivo and in vitro studies of the test substance, structurally related compounds, or therapeutic class. When relevant information is unavailable, a more general approach can be applied in safety pharmacology investigations. A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. Cardiovascular, respiratory, and central nervous systems are considered to be the most important ones to assess in safety pharmacology studies. Other organ systems, such as the renal or gastrointestinal systems, the functions of which can
Test Systems Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model; pharmacokinetic profile, species, strain, gender, and age of the experimental animals; the susceptibility, sensitivity, and reproducibility of the test system; and available background data on the substance. Data from humans (e.g., in vitro metabolism), when available, should also be considered in the test system selection. Justification should be provided for the selection of the particular animal model or test system. Ex vivo and in vitro systems can include, but are not limited to, isolated organs and tissues, cell cultures, cellular fragments, subcellular organelles, receptors, ion channels, transporters, and enzymes. In vitro systems can be used in supportive studies, for example, to obtain a profile of the activity of the substance or to investigate the mechanism of effects observed in vivo. The use of the same species is preferred for in vivo tests as those used in drug metabolism, pharmacokinetics, and toxicology – generally, rats and dogs. Appropriate negative and positive control groups are included in the experimental design. The expected clinical route of administration should be used when feasible. Regardless of the route of administration, exposure to the parent substance and its major metabolites should be similar to or greater than that achieved in humans when such information is available.
Dose Levels or Concentrations of Test Substances and Metabolites Safety pharmacology studies are intended to define the dose– response relationship and time course (when feasible) of the adverse effect observed. Since there are species differences in pharmacodynamic sensitivity, doses should include and exceed the primary pharmacodynamic or therapeutic range. In the absence of an adverse effect on the safety pharmacology parameter evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this study or in other studies using similar route and duration. In vitro studies should be designed to establish a concentration–effect relationship. The range of concentrations used
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should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by physicochemical properties of the test substance and other assay-specific factors. In the absence of an effect, the range of concentrations selected should be justified. Although safety pharmacology studies are generally performed by singledose administration, the duration can be modified if warranted by the findings from animal or human studies. Generally, any parent compound and its major metabolite that achieve or are expected to achieve systemic exposure in humans should be evaluated in safety pharmacology studies. Evaluation of major metabolites is often accomplished through studies of the parent compound in animals. Separate safety studies should be conducted with metabolites, if the human metabolite is absent or present at only low concentrations in animals, or if the metabolite is active and contributes to the pharmacological actions of the therapeutic agent.
Safety Pharmacology Core Battery of Tests The purpose of the safety pharmacology core battery of tests is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory, and central nervous systems are usually considered the vital organ systems that should be studied in the core battery of tests. In some instances, based on scientific rationale, the core battery may be supplemented by other tests, or some of the tests may become unnecessary.
Central Nervous System Effects of the test substance on the central nervous system should be assessed appropriately. Motor activity, behavioral changes, coordination, sensory/motor reflex responses, and body temperature should be evaluated. For example, a functional observation battery test, modified Irwin’s test, or other appropriate tests can be used. Protocols for measuring general behavioral signs induced by test substances (Irwin‘s test), effects on spontaneous locomotion (activity meter test), effects on neuromuscular coordination (rotarod test), effects on the convulsive threshold (electroconvulsive shock threshold and pentylenetetrazol (PTZ) seizure tests), interaction with hypnotics (barbital interaction test), and effects on the pain threshold (hot plate test) should be considered as appropriate.
cell lines, potassium channel recordings in heart muscle cell and Purkinje fiber for APD90, and/or monophasic action potential (MAP) measurements are just a few.
Respiratory System The known effects of drugs from a variety of pharmacologic and therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. Effects of the test substance on the respiratory system should be accurately evaluated from several perspectives (physiologically, pharmacologically, toxicologically, not ignoring preexisting and genetic factors). Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation, respiratory rate, minute volume, peak inspiratory flow, peak expiratory flow, and fractional inspiratory time) should be evaluated. Clinical observation of animals is generally not adequate to assess respiratory function, and thus, these parameters should be quantified by using appropriate methodologies. Pumping apparatus defects are classified as hypo- or hyperventilation syndromes and are assessed by examining ventilatory parameters in a conscious animal model. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow–volume and pressure–volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes postdose). The principal goal should be to determine whether a drug has the potential to produce a change in respiratory function and to establish whether this change is a liability. Focus should be on changes that can result from either the primary or secondary pharmacological properties of a drug or from organ dysfunction resulting from the toxicological properties of a drug.
Recent Advances Cardiovascular System Effects of the test substance on the cardiovascular system should be assessed appropriately. Blood pressure, body temperature, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro, or ex vivo evaluations, including methods for repolarization and conductance abnormalities, should also be considered. Electrocardiograms (ECGs), noninvasive cardiovascular assessments in conscious large animals (ECG: multileads/lead II ECGs), blood pressure by high-definition oscillometry, in vitro cardiovascular evaluation by hERG screening in stably transfected HEK293 cells and other
Twenty-first century safety pharmacology has embraced embryonic stem (ES) cells as a model to test and treat human conditions in a variety of ways. ES has the ability to undergo self-renewal and is pluripotent (can give rise to all types of specialized cells in the body). Knowledge on ES cells is expanding rapidly, leading to opportunities for the establishment of ES-cell-based in vitro tests for drug discovery, preclinical safety pharmacology, and toxicology. The main properties of ES cells making them useful in in vitro assays are that they have a normal diploid karyotype and can provide a large number of cells for high-throughput assays. Human ES cells additionally have the potential to provide solutions to
Safety Pharmacology
problems related to interspecies differences and methods for screening human polymorphisms, thus supporting robust human hazard identification and optimized drug discovery strategies. Importantly, ES-cell-based assays could be potential tools to reduce and perhaps replace animal experiments. Incredible amounts of resources are being invested to make full use of ES cells in toxicology and safety pharmacology, focusing on the major areas of progress, namely embryotoxicology, cardiotoxicology, and hepatoxicology. It appears that regulatory science is yet to witness the golden age of safety pharmacology.
Follow-Up and Supplemental Safety Pharmacology Studies When concerns arise for human safety from the safety pharmacology core battery, other studies, clinical trials, and pharmacovigilance, follow-up or supplemental safety pharmacology studies need to be conducted as appropriate. Followup studies are conducted to gain additional information to that provided by core battery. Some of the follow-up evaluations for core battery are central nervous system – behavioral pharmacology, learning and memory, ligand-specific binding, neurochemistry, visual, auditory, and/or electrophysiology examinations, etc.; cardiovascular system – cardiac output, ventricular contractility, vascular resistance, the effects of endogenous and/or exogenous substances on the cardiovascular responses, etc.; and respiratory system – airway resistance, compliance, pulmonary arterial pressure, blood gases, blood pH, etc. Supplemental studies are meant to evaluate potential adverse pharmacodynamic effects on organ system functions not addressed by the core battery of tests or repeated dose toxicity studies when there is a cause for concern. These include specific tests or studies on renal/urinary systems, autonomic nerve system, and gastrointestinal system. When there is a concern on other organ systems other than the mentioned ones, additional studies should be done to assess the safety.
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Conclusions Pharmacology studies have been performed worldwide for many years as part of the nonclinical evaluation of pharmaceuticals for human use. Safety pharmacology studies are focused on identifying adverse effects on physiological functions at therapeutic doses. These studies are necessary to protect not only the patients treated with drugs, but also the healthy volunteers participating in the clinical trials. The 1960s and 1970s saw a rapid increase in laws, regulations, and guidelines for reporting and evaluating the data on safety, quality, and efficacy of new medicinal products. Until recently, although different regulatory systems were based on the same fundamental obligations to evaluate the quality, safety, and efficacy, the detailed technical requirements were different from each other. Because the pharmaceutical industries have to deliver the safe therapeutics rapidly due to many factors, the ICH was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan, and the United States. The ICH guideline on safety pharmacology has been in effect worldwide since 2001. The ICH S7A guideline has brought uniformity to the evaluations of new drugs for effects on organ functions. The effects of a test substance on the functions listed in the safety pharmacology core battery should be investigated prior to first administration in humans. Any follow-up or supplemental studies identified as appropriate, based on a cause for concern, should also be conducted. No simple formula or set of tests is ideal for safety pharmacology studies for all kinds of therapeutic compounds. Knowledge of the pharmacology of the compound and any knowledge gained from traditional toxicity can help to better determine and assess the safety of compounds. Since the ICH S7A guideline provides flexibility in choosing assays required to assess the effects on organ functions, the success of safety pharmacology will depend, in part, on keeping up with scientific advancements.
See also: Safety Testing, Clinical Studies; Toxicity Testing, Validation; Behavioral Toxicology; The International Conference on Harmonisation.
Conditions under Which Studies Are Not Necessary Safety pharmacology studies may not be needed for locally applied agents (e.g., dermal or ocular) where the pharmacology of the test substance is well characterized and where systemic exposure or distribution to other organs or tissues is demonstrated to be low. For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to evaluate safety pharmacology end points as a part of toxicology or pharmacodynamic studies, and therefore, safety pharmacology studies can be reduced or eliminated for these products. In addition, testing is not required for new salts having similar pharmacokinetics and pharmacodynamics and cytotoxic agents for treatment of end-stage cancer patients. However, for cytotoxic agents and biotechnology-derived products that represent a novel therapeutic class or mechanism of action or that do not achieve high receptor-specific targeting, extensive safety pharmacology studies described should be considered.
Further Reading Authier, S., Vargas, H.M., Curtis, M.J., Holbrook, M., Pugsley, M.K., 2013. Safety pharmacology investigations in toxicology studies: an industry survey. J. Pharmacol. Toxicol. Methods 68 (1), 44–51. Cavero, I., 2012. Annual meeting of the safety pharmacology society: spotlight on targeted oncology medicines. Expert Opin. Drug Saf. 12 (4), 589–603. Ewart, L., Gallacher, D.J., Gintant, G., et al., 2012. How do the top 12 pharmaceutical companies operate safety pharmacology? J. Pharmacol. Toxicol. Methods 66 (2), 66–70. Ewart, L., Milne, A., Adkins, D., Benjamin, A., et al., 2013. A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A &B regulatory submissions. J. Pharmacol. Toxicol. Methods 68 (1), 30–43. Gad, S.C., 2003. Safety Pharmacology in Pharmaceutical Development and Approval. CRC Press, New York. Himmel, H.M., 2008. Safety pharmacology assessment of central nervous system function in juvenile and adult rats: effects of pharmacological reference compounds. J. Pharmacol. Toxicol. Methods 58 (2), 129–146.
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Kraushaar, U., Meyer, T., Hess, D., et al., 2012. Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models. Expert Opin. Drug Saf. 11 (2), 285–298. Leishman, D.J., Beck, T.W., Dybdal, N., et al., 2012. Best practice in the conduct of key nonclinical cardiovascular assessments in drug development: current recommendations from the safety pharmacology society. J. Pharmacol. Toxicol. Methods 65 (3), 93–101. Porsolt, R.D., 2013. The usefulness of non-human primates in central nervous system safety pharmacology. J. Pharmacol. Toxicol. Methods 68 (1), 23–29. Pugsley, M.K., Authier, S., Curtis, M.J., July–August 2013. Back to the future: safety pharmacology methods and models in 2013. J. Pharmacol. Toxicol. Methods 68 (1), 1–6. Stummann, T.C., Bremer, S., 2012. Embryonic stem cells in safety pharmacology and toxicology. Adv. Exp. Med. Biol. 745, 14–25. Vargas, H.M., Amouzadeh, H.R., Engwall, M.J., 2013. Nonclinical strategy considerations for safety pharmacology: evaluation of biopharmaceuticals. Expert Opin. Drug Saf. 12 (1), 91–102.
Relevant Websites http://www.criver.com/products-services/safety-assessment/toxicology/safetypharmacology – Charles River. http://www.covance.com/products/nonclinical/safety-pharmacology/ – Covance Laboratories.
http://www.ich.org/about/vision.html – International Conference on Harmonisation. http://www.medscape.com/viewarticle/573754_4 – Medscape. http://www.mpiresearch.com/safety-pharmacology/ – MPI Laboratories. http://www.lrri.org/cardiopulmonary-and-safety-pharmacology.aspx – Lovelace Respiratory Research Institute. http://www.ncbi.nlm.nih.gov/pubmed/21689769 – Pubmed – National Library of Medicine. http://www.sri.com/research-development/pharmacokinetics – SRI International. http://www.fda.gov – US Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm074959.pdf – US Food and Drug Administration. http://www.safetypharmacology.org/whatisSP.asp – Safety Pharmacology Society What is Safety Pharmacology.
Definition of Safety Pharmacology Safety pharmacology is defined as the subdivision of pharmacology that investigates the potentially undesirable pharmacodynamic effects on physiological functions in relation to exposure in the therapeutic range and above in determining whether and how (dose regime, subject selection) a new drug can be administered safely to human subjects.
Background Successful drug development requires precise drug safety assessment. The importance of evaluating the safety of medicinal products before they are allowed on the market was realized following unacceptable levels of unanticipated deaths occurring after drugs have entered the market. The eventual regulatory requirements were reached at different times in different regions. A tragic mistake in the formulation of a children’s syrup in the 1930s in the United States and the thalidomide tragedy in the 1960s in Europe are some examples that triggered the regulations requiring product authorization. Traditionally, drug safety studies are designed to examine effects other than the primary therapeutic effect of a drug candidate. While these studies evaluate the toxic profile of the drug candidate at maximum tolerated dose and in selected organs, the effects on normal physiological functions at therapeutic doses have long been neglected. Deaths and adverse effects of drugs have been reported in patients and clinical trial participants due to failure in physiologic functions. Pharmacoepidemiology studies in Europe and the United States have shown that adverse drug reaction accounts for up to 10% of admissions in hospitals. In the United States, from 1954 until 1980, 7 million people participated in clinical trials. Safety pharmacology studies are developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources. Until recently, there have been no internationally accepted definitions, objectives, or recommendations on the design and conduct of safety pharmacology studies. The harmonization in regulation was impelled by concerns over rising costs of health care, escalation of the cost of research and development, and the need to meet the public expectation that there should be a minimum of delay in making safe and efficacious new treatments available to patients in need. In 1990, representatives of the regulatory agencies and industry associations of Europe, Japan, and the United States proposed the International Conference on Harmonization (ICH) to develop harmonized guidance on technical issues aimed at ensuring that good-quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest
198
of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans, and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. The ICH guideline on safety pharmacology (ICH S7A) was recommended for adoption by regulatory bodies in the European Union, United States, and Japan in November 2000, and it has been in effect worldwide since 2001. With this guideline calling for tests on the effects of compounds on vital functions of the human body, the data providing specific information on the safety profile of a new potential therapeutic agent used by clinicians designing clinical studies and by regulatory agencies in their assessment of the safety of a new product are crucial. A brief description of the safety pharmacology studies is presented in this article. Genetic profiling early in a drug0 s development to study variations in pharmacokinetic and pharmacodynamic profiles would help correlate genetic biomarkers with drug response. Pharmacogenomics and pharmacokinetics together with progress in genetic biotechnology are starting to change the approach to drug discovery for the treatment of complex diseases. Thus, it can be affirmatively predicted that efficiency in drug development, and safety and efficacy in drug administration, can be gained from coordinated collection of pharmacogenetic data. The transparency, quality, and completeness of genetic data collected from patients will determine the pace at which new drugs will be discovered and brought safely to market. Efforts and close coordination between the US Food and Drug Administration (FDA), research institutes, clinicians, and pharmaceutical companies are already optimal. Pending legislation in the US Congress holds great potential to facilitate a faster and more transparent approval process for new drugs, while providing improved corresponding diagnostic tests. The Role of Safety Pharmacology in a Regulatory Agency (FDA)*
Safety pharmacology studies, which investigate potential undesirable pharmacodynamic effects of a test substance on physiological function in relation to exposure, play an important role in determining whether and how (dose regime, subject selection) a novel test substance can be administered safely to human subjects. Core studies on key systems (central nervous, respiratory, and cardiovascular systems) constitute an important component of the initial safety evaluation, and are reviewed prior to the first administration to human studies. Hazard identification and risk evaluation are key aspects of the evaluation, and can be critical in the design of clinical trials.
Encyclopedia of Toxicology, Volume 4
http://dx.doi.org/10.1016/B978-0-12-386454-3.00352-3
Safety Pharmacology
Pharmacologist/toxicologists are tasked with reviewing safety pharmacology studies, and interact with other members of the review team, which include medical officers, clinical pharmacologists, chemists and project managers. Pharmacologists/ toxicologists also interact with industry scientists to evaluate specific concerns related to mechanism of action and empirical findings seen in other studies or with similar test substances. Source: Safety Pharmacology Society http://www.safetypharmacology.org/ whatisSP.asp.
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be transiently disrupted by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate investigative concern. Safety pharmacology evaluation of effects on these other systems may be of particular importance when considering factors such as the likely clinical trial or patient population, for example, gastrointestinal tract in Crohn’s disease, renal function in primary renal hypertension, and immune system in immunocompromised patients. The safety pharmacology studies should be conducted in compliance with good laboratory practice (GLP). When the studies are not conducted in compliance with GLP, data quality and integrity should be ensured. These safety pharmacology end points can also be obtained from adequately designed and conducted GLP toxicology studies, thereby eliminating the need for separate safety pharmacology studies.
Types of Pharmacological Studies Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies. Studies on the mode of action or effects of a substance in relation to its desired therapeutic target are primary pharmacodynamic studies. Studies on the mode of action or effects of a substance not related to its desired therapeutic target are secondary pharmacodynamic studies. These have sometimes been referred to as part of general pharmacology studies. Safety pharmacology studies critically assess unanticipated effects of new drug candidates on major organ functions at exposures in the therapeutic range and above. Organ systems evaluated primarily are cardiovascular, respiratory, and central nervous systems. The supplemental evaluations are renal/urinary function, gastrointestinal function, and immune function assessment. In addition to these batteries of tests, knowledge of potential harmful interactions or interactions between medications that may neutralize the beneficial effects is becoming increasingly important to evaluate the coadministration of drugs.
Objectives of Safety Pharmacology Studies The objectives of safety pharmacology studies are (1) to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety; (2) to evaluate adverse pharmacodynamic or pathophysiological effects of a substance observed in toxicology or clinical studies; and (3) to investigate the mechanism of the adverse pharmacodynamic effects observed or suspected. The methods used must be validated, well established, should be in common use, and should give reliable, reproducible results every time. The study design should consider the available in vivo and in vitro studies of the test substance, structurally related compounds, or therapeutic class. When relevant information is unavailable, a more general approach can be applied in safety pharmacology investigations. A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. Cardiovascular, respiratory, and central nervous systems are considered to be the most important ones to assess in safety pharmacology studies. Other organ systems, such as the renal or gastrointestinal systems, the functions of which can
Test Systems Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model; pharmacokinetic profile, species, strain, gender, and age of the experimental animals; the susceptibility, sensitivity, and reproducibility of the test system; and available background data on the substance. Data from humans (e.g., in vitro metabolism), when available, should also be considered in the test system selection. Justification should be provided for the selection of the particular animal model or test system. Ex vivo and in vitro systems can include, but are not limited to, isolated organs and tissues, cell cultures, cellular fragments, subcellular organelles, receptors, ion channels, transporters, and enzymes. In vitro systems can be used in supportive studies, for example, to obtain a profile of the activity of the substance or to investigate the mechanism of effects observed in vivo. The use of the same species is preferred for in vivo tests as those used in drug metabolism, pharmacokinetics, and toxicology – generally, rats and dogs. Appropriate negative and positive control groups are included in the experimental design. The expected clinical route of administration should be used when feasible. Regardless of the route of administration, exposure to the parent substance and its major metabolites should be similar to or greater than that achieved in humans when such information is available.
Dose Levels or Concentrations of Test Substances and Metabolites Safety pharmacology studies are intended to define the dose– response relationship and time course (when feasible) of the adverse effect observed. Since there are species differences in pharmacodynamic sensitivity, doses should include and exceed the primary pharmacodynamic or therapeutic range. In the absence of an adverse effect on the safety pharmacology parameter evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this study or in other studies using similar route and duration. In vitro studies should be designed to establish a concentration–effect relationship. The range of concentrations used
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should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by physicochemical properties of the test substance and other assay-specific factors. In the absence of an effect, the range of concentrations selected should be justified. Although safety pharmacology studies are generally performed by singledose administration, the duration can be modified if warranted by the findings from animal or human studies. Generally, any parent compound and its major metabolite that achieve or are expected to achieve systemic exposure in humans should be evaluated in safety pharmacology studies. Evaluation of major metabolites is often accomplished through studies of the parent compound in animals. Separate safety studies should be conducted with metabolites, if the human metabolite is absent or present at only low concentrations in animals, or if the metabolite is active and contributes to the pharmacological actions of the therapeutic agent.
Safety Pharmacology Core Battery of Tests The purpose of the safety pharmacology core battery of tests is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory, and central nervous systems are usually considered the vital organ systems that should be studied in the core battery of tests. In some instances, based on scientific rationale, the core battery may be supplemented by other tests, or some of the tests may become unnecessary.
Central Nervous System Effects of the test substance on the central nervous system should be assessed appropriately. Motor activity, behavioral changes, coordination, sensory/motor reflex responses, and body temperature should be evaluated. For example, a functional observation battery test, modified Irwin’s test, or other appropriate tests can be used. Protocols for measuring general behavioral signs induced by test substances (Irwin‘s test), effects on spontaneous locomotion (activity meter test), effects on neuromuscular coordination (rotarod test), effects on the convulsive threshold (electroconvulsive shock threshold and pentylenetetrazol (PTZ) seizure tests), interaction with hypnotics (barbital interaction test), and effects on the pain threshold (hot plate test) should be considered as appropriate.
cell lines, potassium channel recordings in heart muscle cell and Purkinje fiber for APD90, and/or monophasic action potential (MAP) measurements are just a few.
Respiratory System The known effects of drugs from a variety of pharmacologic and therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. Effects of the test substance on the respiratory system should be accurately evaluated from several perspectives (physiologically, pharmacologically, toxicologically, not ignoring preexisting and genetic factors). Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation, respiratory rate, minute volume, peak inspiratory flow, peak expiratory flow, and fractional inspiratory time) should be evaluated. Clinical observation of animals is generally not adequate to assess respiratory function, and thus, these parameters should be quantified by using appropriate methodologies. Pumping apparatus defects are classified as hypo- or hyperventilation syndromes and are assessed by examining ventilatory parameters in a conscious animal model. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow–volume and pressure–volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes postdose). The principal goal should be to determine whether a drug has the potential to produce a change in respiratory function and to establish whether this change is a liability. Focus should be on changes that can result from either the primary or secondary pharmacological properties of a drug or from organ dysfunction resulting from the toxicological properties of a drug.
Recent Advances Cardiovascular System Effects of the test substance on the cardiovascular system should be assessed appropriately. Blood pressure, body temperature, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro, or ex vivo evaluations, including methods for repolarization and conductance abnormalities, should also be considered. Electrocardiograms (ECGs), noninvasive cardiovascular assessments in conscious large animals (ECG: multileads/lead II ECGs), blood pressure by high-definition oscillometry, in vitro cardiovascular evaluation by hERG screening in stably transfected HEK293 cells and other
Twenty-first century safety pharmacology has embraced embryonic stem (ES) cells as a model to test and treat human conditions in a variety of ways. ES has the ability to undergo self-renewal and is pluripotent (can give rise to all types of specialized cells in the body). Knowledge on ES cells is expanding rapidly, leading to opportunities for the establishment of ES-cell-based in vitro tests for drug discovery, preclinical safety pharmacology, and toxicology. The main properties of ES cells making them useful in in vitro assays are that they have a normal diploid karyotype and can provide a large number of cells for high-throughput assays. Human ES cells additionally have the potential to provide solutions to
Safety Pharmacology
problems related to interspecies differences and methods for screening human polymorphisms, thus supporting robust human hazard identification and optimized drug discovery strategies. Importantly, ES-cell-based assays could be potential tools to reduce and perhaps replace animal experiments. Incredible amounts of resources are being invested to make full use of ES cells in toxicology and safety pharmacology, focusing on the major areas of progress, namely embryotoxicology, cardiotoxicology, and hepatoxicology. It appears that regulatory science is yet to witness the golden age of safety pharmacology.
Follow-Up and Supplemental Safety Pharmacology Studies When concerns arise for human safety from the safety pharmacology core battery, other studies, clinical trials, and pharmacovigilance, follow-up or supplemental safety pharmacology studies need to be conducted as appropriate. Followup studies are conducted to gain additional information to that provided by core battery. Some of the follow-up evaluations for core battery are central nervous system – behavioral pharmacology, learning and memory, ligand-specific binding, neurochemistry, visual, auditory, and/or electrophysiology examinations, etc.; cardiovascular system – cardiac output, ventricular contractility, vascular resistance, the effects of endogenous and/or exogenous substances on the cardiovascular responses, etc.; and respiratory system – airway resistance, compliance, pulmonary arterial pressure, blood gases, blood pH, etc. Supplemental studies are meant to evaluate potential adverse pharmacodynamic effects on organ system functions not addressed by the core battery of tests or repeated dose toxicity studies when there is a cause for concern. These include specific tests or studies on renal/urinary systems, autonomic nerve system, and gastrointestinal system. When there is a concern on other organ systems other than the mentioned ones, additional studies should be done to assess the safety.
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Conclusions Pharmacology studies have been performed worldwide for many years as part of the nonclinical evaluation of pharmaceuticals for human use. Safety pharmacology studies are focused on identifying adverse effects on physiological functions at therapeutic doses. These studies are necessary to protect not only the patients treated with drugs, but also the healthy volunteers participating in the clinical trials. The 1960s and 1970s saw a rapid increase in laws, regulations, and guidelines for reporting and evaluating the data on safety, quality, and efficacy of new medicinal products. Until recently, although different regulatory systems were based on the same fundamental obligations to evaluate the quality, safety, and efficacy, the detailed technical requirements were different from each other. Because the pharmaceutical industries have to deliver the safe therapeutics rapidly due to many factors, the ICH was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan, and the United States. The ICH guideline on safety pharmacology has been in effect worldwide since 2001. The ICH S7A guideline has brought uniformity to the evaluations of new drugs for effects on organ functions. The effects of a test substance on the functions listed in the safety pharmacology core battery should be investigated prior to first administration in humans. Any follow-up or supplemental studies identified as appropriate, based on a cause for concern, should also be conducted. No simple formula or set of tests is ideal for safety pharmacology studies for all kinds of therapeutic compounds. Knowledge of the pharmacology of the compound and any knowledge gained from traditional toxicity can help to better determine and assess the safety of compounds. Since the ICH S7A guideline provides flexibility in choosing assays required to assess the effects on organ functions, the success of safety pharmacology will depend, in part, on keeping up with scientific advancements.
See also: Safety Testing, Clinical Studies; Toxicity Testing, Validation; Behavioral Toxicology; The International Conference on Harmonisation.
Conditions under Which Studies Are Not Necessary Safety pharmacology studies may not be needed for locally applied agents (e.g., dermal or ocular) where the pharmacology of the test substance is well characterized and where systemic exposure or distribution to other organs or tissues is demonstrated to be low. For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to evaluate safety pharmacology end points as a part of toxicology or pharmacodynamic studies, and therefore, safety pharmacology studies can be reduced or eliminated for these products. In addition, testing is not required for new salts having similar pharmacokinetics and pharmacodynamics and cytotoxic agents for treatment of end-stage cancer patients. However, for cytotoxic agents and biotechnology-derived products that represent a novel therapeutic class or mechanism of action or that do not achieve high receptor-specific targeting, extensive safety pharmacology studies described should be considered.
Further Reading Authier, S., Vargas, H.M., Curtis, M.J., Holbrook, M., Pugsley, M.K., 2013. Safety pharmacology investigations in toxicology studies: an industry survey. J. Pharmacol. Toxicol. Methods 68 (1), 44–51. Cavero, I., 2012. Annual meeting of the safety pharmacology society: spotlight on targeted oncology medicines. Expert Opin. Drug Saf. 12 (4), 589–603. Ewart, L., Gallacher, D.J., Gintant, G., et al., 2012. How do the top 12 pharmaceutical companies operate safety pharmacology? J. Pharmacol. Toxicol. Methods 66 (2), 66–70. Ewart, L., Milne, A., Adkins, D., Benjamin, A., et al., 2013. A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A &B regulatory submissions. J. Pharmacol. Toxicol. Methods 68 (1), 30–43. Gad, S.C., 2003. Safety Pharmacology in Pharmaceutical Development and Approval. CRC Press, New York. Himmel, H.M., 2008. Safety pharmacology assessment of central nervous system function in juvenile and adult rats: effects of pharmacological reference compounds. J. Pharmacol. Toxicol. Methods 58 (2), 129–146.
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Kraushaar, U., Meyer, T., Hess, D., et al., 2012. Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models. Expert Opin. Drug Saf. 11 (2), 285–298. Leishman, D.J., Beck, T.W., Dybdal, N., et al., 2012. Best practice in the conduct of key nonclinical cardiovascular assessments in drug development: current recommendations from the safety pharmacology society. J. Pharmacol. Toxicol. Methods 65 (3), 93–101. Porsolt, R.D., 2013. The usefulness of non-human primates in central nervous system safety pharmacology. J. Pharmacol. Toxicol. Methods 68 (1), 23–29. Pugsley, M.K., Authier, S., Curtis, M.J., July–August 2013. Back to the future: safety pharmacology methods and models in 2013. J. Pharmacol. Toxicol. Methods 68 (1), 1–6. Stummann, T.C., Bremer, S., 2012. Embryonic stem cells in safety pharmacology and toxicology. Adv. Exp. Med. Biol. 745, 14–25. Vargas, H.M., Amouzadeh, H.R., Engwall, M.J., 2013. Nonclinical strategy considerations for safety pharmacology: evaluation of biopharmaceuticals. Expert Opin. Drug Saf. 12 (1), 91–102.
Relevant Websites http://www.criver.com/products-services/safety-assessment/toxicology/safetypharmacology – Charles River. http://www.covance.com/products/nonclinical/safety-pharmacology/ – Covance Laboratories.
http://www.ich.org/about/vision.html – International Conference on Harmonisation. http://www.medscape.com/viewarticle/573754_4 – Medscape. http://www.mpiresearch.com/safety-pharmacology/ – MPI Laboratories. http://www.lrri.org/cardiopulmonary-and-safety-pharmacology.aspx – Lovelace Respiratory Research Institute. http://www.ncbi.nlm.nih.gov/pubmed/21689769 – Pubmed – National Library of Medicine. http://www.sri.com/research-development/pharmacokinetics – SRI International. http://www.fda.gov – US Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm074959.pdf – US Food and Drug Administration. http://www.safetypharmacology.org/whatisSP.asp – Safety Pharmacology Society What is Safety Pharmacology.