Safety pharmacology

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safety pharmacology


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SAFETY PHARMACOLOGY STUDIES FOR HUMAN PHARMACEUTICALS Presented by Shweta Thakur 2 nd semester Pharmacology Department of pharmaceuticals and sciences


CONTENT 1. INTRODUCTION 1.1 Objectives of the Guideline 1.2 Background 1.3 Scope of the Guideline 1.4 General Principle 1.5 Definition of Safety Pharmacology 2. GUIDELINE 2.1 Objectives of Studies 2.2 General Considerations in Selection and Design of Safety Pharmacology Studies 2.3 Test Systems 2.4 Dose Levels or Concentrations of Test Substance


2.5 Duration of Studies 2.6 Safety Pharmacology Core Battery 2.7 Follow-up and Supplemental Safety Pharmacology Studies 2.8 Conditions under which Studies are not Necessary 2.9 Timing of Safety Pharmacology Studies in Relation to Clinical Development


MAJOR POINTS IN GUIDELINES Definition Rational Approach Core Battery, Follow-up and Supplemental Safety Pharmacology Studies Based on Hierarchical Order of Organ Systems Investigation in Relation to Systemic Exposure Considerations for Dose Selection Timing in Relation to Clinical Development GLP Application


DEFINATION Safety P harmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamics effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. Sometimes the primary and secondary pharmacodynamics properties of the substance may contribute to the safety evaluation for potential adverse effect(s) in humans . Primary pharmacodynamics :- Studies on the mode of action and or effects in relation to the desired therapeutic target. Secondary pharmacodynamics :- Studies on the mode of action and/or effects not related to the desired therapeutic target.


INTRODUCTUION GENERAL PRINCIPLE :- Rational Approach in Design and Conduct Based on Pharmaceutical’s Properties and Uses. Scientifically Valid Methods . Use of New Technologies and Methodologies is Encouraged. Potential to Incorporate SP End points into Toxicology, Kinetics, Clinical studies etc.


BACKGROUND :- Pharmacology studies have been performed worldwide for many years as part of the non-clinical evaluation of pharmaceuticals for human use. There have been, however, no internationally accepted definitions, objectives or recommendations on the design and conduct of safety pharmacology studies. The term “safety pharmacology studies” first appeared in the ICH topics, “Timing of Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals ” and “Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals ” as studies that should be conducted to support use of therapeutics in humans.


SCOPE :- It mainly applies to * New chemical entities. * Biotechnology-derived products. * Marketed pharmaceuticals when appropriate.


GUIDELINES OBJECTIVES :- T o identify undesirable pharmacodynamics properties of a substance that may have relevance to its human safety . T o evaluate adverse pharmacodynamics and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies. T o investigate the mechanism of the adverse pharmacodynamics effects observed and/or suspected. The investigational plan to meet these objectives should be clearly identified and delineated.


General Considerations in Selection and Design of Safety Pharmacology Studies :- The following factors should be considered (the list is not comprehensive ):- * Effects related to the therapeutic class of the test substance, since the mechanism of action may suggest specific adverse effects. e.g ., proarrhythmia is a common feature of antiarrhythmic agents * Adverse effects associated with members of the chemical or therapeutic class, but independent of the primary pharmacodynamics effects. e.g ., anti-psychotics and QT prolongation * Ligand binding or enzyme assay data suggesting a potential for adverse effects .


Continue……….. * Results from previous safety pharmacology studies, from secondary pharmacodynamics studies, from toxicology studies, or from human use that warrant further investigation to establish and characterize the relevance of these findings to potential adverse effects in humans . * During early development, sufficient information (e.g., comparative metabolism) may not always be available to rationally select or design the studies in accordance with the points stated above; in such circumstances, a more general approach in safety pharmacology investigations can be applied. A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. * Vital organs or systems, the functions of which are acutely critical for life, such as the 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 system, the functions of which can be transiently disrupted by adverse pharmacodynamics 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 .


TEST SYSTEM :- General consideration on test system : * General consideration on selection of animal model should include:- - the pharmacodynamics responsiveness of the model - pharmacokinetic profile - species - strain - gender - age - the susceptibility - sensitivity - reproducibility of the test system and available background data on the substance .


The time point for the measurement of human should be based on :- Pharmacokinetic factor Pharmacodynamics factor


Use of In Vivo and In Vitro Studies :- Animal models as well as ex vivo and in vitro preparations can be used as test systems. Ex vivo and in vitro systems can include : * isolated organs and tissues * cell cultures * c ell organelles * subcellular organelles etc.


In vivo animal include : * unanaesthetized animals * Data from unrestrained animals used for telemetry. * For unanesthetized animals, the avoidance of discomfort or pain is a foremost consideration.


Experimental Design :- * Sample Size and Use of Controls : * Size of the groups :- should be sufficient to allow meaningful scientific interpretation. * No. of animal should be adequate. * Negative and positive control groups should be included ; positive group may not be necessary. * Exclusion of controls from studies should be justified.


Route of Administration :- C linical route of administration should be used . E xposure to the parent substance and its major metabolites should be similar to that achieved in humans. If clinical use involves multiple routes, consider more than one route.


Dose Levels or Concentrations of Test Substance :- In Vivo Studies : * Safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed. * Generally , the doses eliciting the adverse effect should be compared to the doses eliciting the primary pharmacodynamics effect in the test species or the proposed therapeutic effect in humans, if feasible . * It is recognized that there are species differences in pharmacodynamic sensitivity. Therefore, doses should include and exceed the primary pharmacodynamic or therapeutic range.


* In the absence of an adverse effect on the safety pharmacology parameter(s) evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this or in other studies of similar route and duration. These adverse effects can include dose-limiting pharmacodynamics effects or other toxicity. * Testing of a single group at the limiting dose as described above may be sufficient in the absence of an adverse effect on safety pharmacology endpoints in the test species.


In Vitro Studies : It should be designed to establish a concentration-effect relationship. The range of concentrations used 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 physico -chemical properties of the test substance and other assay specific factors. In the absence of an effect, the range of concentrations selected should be justified.


Duration of Studies :- * Safety pharmacology studies are generally performed by single dose administration . * The duration of the safety pharmacology studies to address the following effects should be rationally based on : * When pharmacodynamic effects occur only after a certain duration of treatment. * When results from repeat dose non-clinical studies . * Results from use in humans give rise to concerns about safety pharmacological effects.


Safety Pharmacology Core Battery :- The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. Vital organs are :- * Central Nervous system * Cardiovascular system * Respiratory system The exclusion of certain test(s) or exploration(s) of certain organs, systems or functions should be scientifically justified.


* Central nervous system Effects of the test substance on the central nervous system should be assessed appropriately it may be as follow:- - Motor activity - behavioral changes - coordination - sensory/motor reflex responses - body temperature * Cardiovascular system Following effects of the test substance on the cardiovascular system should be assessed appropriately it may be as follow :- - Blood pressure - heart rate - electrocardiogram


* Respiratory system Following effects of the test substance on the respiratory system should be assessed appropriately it may be follow as :- - tidal volume - hemoglobin oxygen saturation etc.


Follow-up and Supplemental Safety Pharmacology Studies :- It should consider when : * Adverse effects may be suspected based on the pharmacological properties or chemical class * Additionally, concerns may arise from the safety pharmacology core battery, clinical trials, pharmacovigilance, experimental in vitro or in vivo studies, or from literature reports.


* Follow-up Studies :- - These studies should be selected on the basis of case-by-case study. - Should provide a great depth of understanding - List that provided should not be comprehensive and prescriptive . - In some cases, it may be more appropriate to address these effects during the conduct of other non-clinical and/or clinical studies. * Supplemental Safety Pharmacology Studies :- -Supplemental studies are meant to evaluate potential adverse pharmacodynamics effects on organ system functions not addressed by the core battery i.e., Renal/Urinary System Autonomic Nervous System Gastrointestinal System Other Organ Systems


Renal/Urinary System Following effect should be assessed :- - urinary volume - specific gravity - osmolality - pH - fluid/electrolyte balance - proteins Autonomic Nervous System Following effect should be assessed :- - binding to receptors relevant for the autonomic nervous system - functional responses to agonists or antagonists in vivo or in vitro - baroreflex testing etc.


Gastrointestinal System Following effect should be assessed :- - gastric secretion - gastrointestinal injury potential - bile secretion - transit time in vivo - ileum contraction in vitro - gastric pH measurement and pooling Other Organ Systems F ollowing effect should be assessed:- - dependency potential - skeletal muscle, - immune and endocrine functions


Conditions under which Studies are not Necessary :- Some locally applied agents (e.g. dermal or ocular) Some cytotoxic agents for treatment of end-stage cancer patients. Some biotechnology-derived products


Timing of Safety Pharmacology Studies in Relation to Clinical Development :- When planning a safety pharmacology program, section 2.9 should be reviewed to determine whether or not specific studies are recommended. * Studies Prior to First Administration in Humans :- - 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. - Information from toxicology studies adequately designed and conducted to address safety pharmacology endpoints can result in reduction or elimination of separate safety pharmacology studies.


* Studies During Clinical Development :- - Additional studies may be warranted to clarify observed or suspected adverse effects in animals and humans during clinical development. * Studies Before Approval :- - Safety pharmacology effects on systems should be assessed prior to product approval, unless not warranted, in which case this should be justified. - Available information from toxicology studies adequately designed and conducted to address safety pharmacology endpoints, or information from clinical studies, can support this assessment and replace safety pharmacology studies.



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