This presentation provides a knowledge about Safety Pharmacology, It's aim & objectives, issues, consideration in selection and design of study and test study, duration of study, various studies involved in safety pharmacology, its guidelines, preclinical safety pharmacology. An assignment for the subject, Clinical Research and Pharmacovigilance, 1st year M.Pharm, 2nd semester.
Safety pharmacology is a branch of pharmacology with its aim to predict the potential clinical risk profile of new chemical entities (NCEs).
It has the ability to predict the potential off-target drug effects on major organ systems which are associated with exposure in the therapeutic range and above.
As an essential part of the spectrum of drug discovery and development, safety pharmacology studies are generally conducted to determine the relative drug effect on main organs, including respiratory system, central nervous system, and cardiovascular system.Safety pharmacology is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials.
SP studies are described in the international conference on harmonization (ICH) S7A and S7B Guidelines.
TOXICOKINETICS EVALUATION IN PRECLINICAL STUDIES.pptxAnmolkanda06
This document discusses toxicokinetics evaluation and saturation kinetics in preclinical studies. It defines toxicokinetics and its primary and secondary objectives in preclinical testing according to ICH guidelines. It outlines the general principles and types of toxicokinetic studies conducted at different stages of preclinical development, including safety assessment studies, single/rising dose studies, repeated dose toxicity studies, genotoxicity studies, reproduction toxicity studies, and carcinogenicity studies. It also discusses saturation kinetics, how non-linear pharmacokinetics can occur due to saturation of absorption, distribution, metabolism or excretion processes, and how non-linearity is detected.
This document discusses the requirements for an investigational new drug (IND) application. An IND is required to initiate clinical trials of an unapproved drug and must contain information on animal studies, manufacturing, and clinical trial protocols. The core battery of safety pharmacology studies evaluates effects on major organ systems like the cardiovascular, central nervous, and respiratory systems. These studies are designed to identify potential adverse effects and safety risks before human clinical trials.
This document summarizes a seminar on safety pharmacology. It defines safety pharmacology and outlines the core battery of studies, which evaluate effects on the central nervous, cardiovascular and respiratory systems. It describes when safety pharmacology studies are needed at different stages of drug development and under various conditions. Guidelines for conducting the studies from organizations like ICH are also discussed.
This document provides guidelines for safety pharmacology studies for human pharmaceuticals from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidelines discuss the objectives, scope, general principles, test systems, experimental design, dose levels/concentrations, duration of studies, and studies on metabolites for safety pharmacology evaluations. The goal is to help protect clinical trial participants and patients by identifying potential adverse effects of pharmaceuticals early in development.
This document discusses safety pharmacology studies, with a focus on respiratory and central nervous system safety pharmacology. It defines safety pharmacology studies as investigating potential undesirable pharmacological effects of substances on physiological functions. For respiratory safety pharmacology, the core battery studies measure respiratory rate, tidal volume, and oxygen saturation. Supplementary studies measure airway resistance and lung compliance. For CNS safety pharmacology, core studies evaluate behavior, locomotor activity, motor coordination, and seizure liability. Safety pharmacology aims to identify risks and inform safe starting doses in clinical trials.
Safety pharmacology is a branch of pharmacology with its aim to predict the potential clinical risk profile of new chemical entities (NCEs).
It has the ability to predict the potential off-target drug effects on major organ systems which are associated with exposure in the therapeutic range and above.
As an essential part of the spectrum of drug discovery and development, safety pharmacology studies are generally conducted to determine the relative drug effect on main organs, including respiratory system, central nervous system, and cardiovascular system.Safety pharmacology is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials.
SP studies are described in the international conference on harmonization (ICH) S7A and S7B Guidelines.
TOXICOKINETICS EVALUATION IN PRECLINICAL STUDIES.pptxAnmolkanda06
This document discusses toxicokinetics evaluation and saturation kinetics in preclinical studies. It defines toxicokinetics and its primary and secondary objectives in preclinical testing according to ICH guidelines. It outlines the general principles and types of toxicokinetic studies conducted at different stages of preclinical development, including safety assessment studies, single/rising dose studies, repeated dose toxicity studies, genotoxicity studies, reproduction toxicity studies, and carcinogenicity studies. It also discusses saturation kinetics, how non-linear pharmacokinetics can occur due to saturation of absorption, distribution, metabolism or excretion processes, and how non-linearity is detected.
This document discusses the requirements for an investigational new drug (IND) application. An IND is required to initiate clinical trials of an unapproved drug and must contain information on animal studies, manufacturing, and clinical trial protocols. The core battery of safety pharmacology studies evaluates effects on major organ systems like the cardiovascular, central nervous, and respiratory systems. These studies are designed to identify potential adverse effects and safety risks before human clinical trials.
This document summarizes a seminar on safety pharmacology. It defines safety pharmacology and outlines the core battery of studies, which evaluate effects on the central nervous, cardiovascular and respiratory systems. It describes when safety pharmacology studies are needed at different stages of drug development and under various conditions. Guidelines for conducting the studies from organizations like ICH are also discussed.
This document provides guidelines for safety pharmacology studies for human pharmaceuticals from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidelines discuss the objectives, scope, general principles, test systems, experimental design, dose levels/concentrations, duration of studies, and studies on metabolites for safety pharmacology evaluations. The goal is to help protect clinical trial participants and patients by identifying potential adverse effects of pharmaceuticals early in development.
This document discusses safety pharmacology studies, with a focus on respiratory and central nervous system safety pharmacology. It defines safety pharmacology studies as investigating potential undesirable pharmacological effects of substances on physiological functions. For respiratory safety pharmacology, the core battery studies measure respiratory rate, tidal volume, and oxygen saturation. Supplementary studies measure airway resistance and lung compliance. For CNS safety pharmacology, core studies evaluate behavior, locomotor activity, motor coordination, and seizure liability. Safety pharmacology aims to identify risks and inform safe starting doses in clinical trials.
TEST ITEM CHARACTERIZATION IN REGULATORY TOXICOLOGY STUDIES.pptxashharnomani
This document provides guidance on the characterization of test items used in regulatory toxicology studies according to OECD GLP principles. It defines key terms like test item, batch, vehicle, and formulation. It describes the importance of characterizing test items to confirm their identity and suitability for studies. Guidance is provided on characterizing specific types of test items like those in early development, living organisms, medical devices, and radiolabeled items. The characterization should include information on the test item's source, composition, and relevant properties.
The document discusses safety pharmacology studies that are conducted to evaluate potential adverse effects of pharmaceutical substances on vital organ systems. It describes the safety pharmacology core battery that investigates effects on the central nervous, cardiovascular and respiratory systems. Follow up studies provide more in-depth understanding of effects on these systems. Supplemental studies evaluate effects on other organ systems like renal, gastrointestinal and immune systems. A variety of evaluation methods are used like functional observation, electrocardiography, plethysmography and biomarkers. Conditions where safety pharmacology studies may not be needed are also outlined.
test item characterization of regulatory of toxicological studies SonaliJain736101
This document provides guidance on characterizing test items used in regulatory toxicology studies conducted in compliance with Good Laboratory Practice principles. It discusses the expectations for characterizing test items regarding transportation, receipt, identification, labeling, sampling, handling, storage, and disposal. The level of characterization may vary depending on the test item, study objectives, and development stage. Characterization should confirm the test item's identity and suitability for the study. Living organisms and medical devices may require unique characterization information. The document aims to promote a consistent approach to test item characterization across studies.
Toxicokinetic evaluation in preclinical studies.pptxARSHIKHANAM4
1. Toxicokinetics is the study of how toxic substances are affected by the body in terms of absorption, distribution, metabolism, and excretion. It applies pharmacokinetic principles to doses used in toxicology testing.
2. The primary objective of toxicokinetic evaluation in preclinical studies is to describe systemic exposure levels in animals and relate this to toxicity findings to assess clinical safety. Secondary objectives include supporting species and dose selection for toxicity studies.
3. Toxicokinetic data is collected in various required preclinical safety studies, including repeat-dose toxicity studies, reproduction toxicity studies, and genotoxicity studies, to interpret results and demonstrate drug exposure.
This document discusses methods for assessing drug effects on renal and gastrointestinal systems in safety pharmacology studies. For renal function, in vivo mammalian models using rats and dogs are commonly used to assess glomerular function through clearance tests, tubular function through urine analysis, and hemodynamic function through blood flow measurements. In vitro and in silico models are also discussed. For gastrointestinal function, methods described include assessing gastric emptying and intestinal motility using in vitro tissue/organ baths and in vivo animal models, measuring gastric secretion in cell preparations and ligated rats, modeling nausea and emesis in ferrets and dogs, and measuring absorption in Caco-2 cell cultures and perfused intestinal segments of rats.
The document outlines the studies needed for an Investigational New Drug (IND) submission to the FDA. An IND application must contain information on animal pharmacology and toxicology studies, chemistry and manufacturing, and clinical protocols. It provides a flow chart showing the various preclinical studies required, including chemical and physical properties, biological studies, pharmacology, toxicology, and formulation studies. The goal of the preclinical studies is to generate data for the safety assessment of the new drug in humans.
Toxicokinetic evaluation in preclinical studies.pptxashharnomani
Toxicokinetic studies aim to understand what the body does with a drug at high doses. Such studies measure parameters like maximum plasma concentration, time to maximum concentration, and area under the plasma concentration curve. Toxicokinetic data from preclinical studies can be used to select appropriate doses and dosing routes for clinical trials and to interpret toxicity findings. Factors like protein binding, metabolism, and species differences must be considered when evaluating toxicokinetic data.
The document describes the hERG assay, which is used to test for potential drug-induced prolongation of the QT interval. It discusses the hERG gene and potassium channel, how mutations can cause long QT syndrome. It then summarizes three methods for conducting the hERG assay: electrophysiological assay using whole-cell patch clamping, Fluorometric imaging plate reader-based thallium flux assay, and radioligand binding with 35S-MK-499. Details are provided on cell preparation and protocol for each type of hERG assay.
Alternative methods to animals testing are the development and implementation of test method that avoid use of live animals or use of less animals in method.
The council directive on protection of animals used for experiments and scientific purpose in article 23
“The commission and member states should encourage
research into development and validation of alternative methods which could provide the same level of information as that obtained in experiment using animals but which involves less animal”.
Alternative methods able to do:
Reduce Refine Replace
collectively called as “The 3Rs Principle”.
Needs for alternative methods
Because in laboratory animals may be:
Poisoned.
Deprived of food water and sleep.
Applied with skin and eye irritants.
Subjected to psychological stress.
Deliberately infected with the infected disease.
Safety pharmacology studies are conducted to help protect clinical trial participants and patients from potential adverse effects of pharmaceuticals. The objectives are to adopt a rational approach in study design and conduct based on a drug's properties and intended uses. Safety pharmacology focuses on detecting undesirable pharmacodynamic effects of new drugs on physiological functions like the central nervous, cardiovascular and respiratory systems. Studies are generally conducted using relevant animal models or test systems to derive scientifically valid information. Results inform subsequent toxicology, kinetics and clinical studies.
IND (Investigational New Drug) industrial perspectiveAYESHA NAZEER
Describing the Industry's/sponsor's/drug manufacturers' perspective of the Investigational New Drug Application (IND) program based on the survey conducted by the Office Of Inspector General (OIG).
Herg assay,Structure, Various screening methods and AdvantagesUrvashi Shakarwal
The document discusses hERG assays, which are used to screen for compounds that may block the hERG potassium channel and prolong the heart's QT interval, potentially causing fatal arrhythmias. It describes the structure and function of the hERG channel, then summarizes various screening methods for hERG activity including electrophysiology, flux assays, fluorescence-based assays, and radioligand binding assays. These methods allow high-throughput screening of large numbers of compounds early in drug development to improve cardiovascular safety.
chronic dermal and inhalational studies as per OECDSohil Shah
This document presents guidelines for chronic toxicity studies as outlined by the OECD. It discusses the objectives of chronic toxicity studies which are to identify hazardous properties, target organs, dose responses, and predict chronic effects in humans. It describes principles such as administering test substances daily to rodents for 12 months to observe toxicity. It provides details on housing, feeding conditions, procedures, observations, and reporting of results for chronic dermal and inhalation studies.
The document provides an overview of the regulatory process for bringing a new drug to market, beginning with pre-clinical studies and submission of an Investigational New Drug (IND) application to the FDA. If approved, the IND allows clinical trials to be conducted in three phases to evaluate safety and efficacy. If phase 3 trials demonstrate a drug is safe and effective, a New Drug Application or Biologics License Application can be submitted for approval to market the drug. Ongoing monitoring of safety continues even after approval.
The document discusses the Investigational New Drug (IND) application process with the FDA. An IND application allows a company to ship an experimental drug across state lines and begin clinical trials. It must include preclinical data to show the drug is safe for initial human use as well as protocols for proposed studies. The FDA reviews the IND for 30 days before clinical trials may begin to ensure subject safety. The overall goal of an IND is to facilitate testing of new drugs while protecting clinical trial participants.
Alternative methods to animal toxicity testingSachin Sharma
This document presents information on alternative methods to animal toxicity testing. It discusses the need for alternatives due to the harms animals face in toxicity testing. The 3Rs principles of reduction, refinement and replacement are explained, which aim to minimize animal use and suffering. The validation process for new alternative methods through organizations like ECVAM is covered. Specific alternative methods mentioned include in vitro tests like the Ames test and HET-CAM test, in silico methods, and mathematical models. The HET-CAM test for eye irritation is described in more detail.
Toxicokinetic evaluation in preclinical studies by Shivam Diwaker Shivam Diwaker
Toxicokinetics evaluation in preclinical studies was presented. The presentation covered absorption, distribution, biotransformation and excretion of chemicals. Key points included how toxicokinetics quantifies exposure through measures like volume of distribution and clearance. The importance of evaluating metabolites and the factors influencing distribution and metabolism were discussed. Toxicokinetic studies are conducted at various stages of preclinical and clinical development to interpret toxicity results and support human trials. Alternative approaches to decrease animal usage in toxicokinetics were also presented.
Aris G is a leading pharmacovigilance system that enables companies to reduce safety risks for drugs, devices, vaccines and combination products. It improves case processing workflows and integrates with other systems. Vigi Flow is an ICSR management system developed by UMC that allows entry, assessment, storage and transmission of safety reports in accordance with ICH E2B standards. Both systems provide features for adverse event reporting, but Vigi Flow is web-based while Aris G can be installed locally.
OECD principles of Good laboratory practice. this ppt include the basic and necessary information required for OECD GLP guideline . Content is taken from official site
This document provides guidelines for safety pharmacology studies for human pharmaceuticals. It defines safety pharmacology as studies investigating potential undesirable pharmacological effects on physiological functions. The guidelines describe a core battery of studies on the central nervous, cardiovascular and respiratory systems to be conducted prior to first human administration. Follow up and supplemental studies may be warranted based on properties, class effects or safety concerns. The timing of studies in relation to clinical development is outlined.
Safety pharmacology studies investigate potential undesirable effects of new drugs on physiological functions like the central nervous, cardiovascular, and respiratory systems. The objectives are to protect clinical trial participants and patients from adverse effects. Core battery studies evaluate effects on vital organ systems, while follow-up studies provide more depth. Supplemental studies explore other organ systems if a cause for concern exists. Timing of studies is before and during clinical development. Studies may be reduced or eliminated based on product characteristics or information from toxicology.
TEST ITEM CHARACTERIZATION IN REGULATORY TOXICOLOGY STUDIES.pptxashharnomani
This document provides guidance on the characterization of test items used in regulatory toxicology studies according to OECD GLP principles. It defines key terms like test item, batch, vehicle, and formulation. It describes the importance of characterizing test items to confirm their identity and suitability for studies. Guidance is provided on characterizing specific types of test items like those in early development, living organisms, medical devices, and radiolabeled items. The characterization should include information on the test item's source, composition, and relevant properties.
The document discusses safety pharmacology studies that are conducted to evaluate potential adverse effects of pharmaceutical substances on vital organ systems. It describes the safety pharmacology core battery that investigates effects on the central nervous, cardiovascular and respiratory systems. Follow up studies provide more in-depth understanding of effects on these systems. Supplemental studies evaluate effects on other organ systems like renal, gastrointestinal and immune systems. A variety of evaluation methods are used like functional observation, electrocardiography, plethysmography and biomarkers. Conditions where safety pharmacology studies may not be needed are also outlined.
test item characterization of regulatory of toxicological studies SonaliJain736101
This document provides guidance on characterizing test items used in regulatory toxicology studies conducted in compliance with Good Laboratory Practice principles. It discusses the expectations for characterizing test items regarding transportation, receipt, identification, labeling, sampling, handling, storage, and disposal. The level of characterization may vary depending on the test item, study objectives, and development stage. Characterization should confirm the test item's identity and suitability for the study. Living organisms and medical devices may require unique characterization information. The document aims to promote a consistent approach to test item characterization across studies.
Toxicokinetic evaluation in preclinical studies.pptxARSHIKHANAM4
1. Toxicokinetics is the study of how toxic substances are affected by the body in terms of absorption, distribution, metabolism, and excretion. It applies pharmacokinetic principles to doses used in toxicology testing.
2. The primary objective of toxicokinetic evaluation in preclinical studies is to describe systemic exposure levels in animals and relate this to toxicity findings to assess clinical safety. Secondary objectives include supporting species and dose selection for toxicity studies.
3. Toxicokinetic data is collected in various required preclinical safety studies, including repeat-dose toxicity studies, reproduction toxicity studies, and genotoxicity studies, to interpret results and demonstrate drug exposure.
This document discusses methods for assessing drug effects on renal and gastrointestinal systems in safety pharmacology studies. For renal function, in vivo mammalian models using rats and dogs are commonly used to assess glomerular function through clearance tests, tubular function through urine analysis, and hemodynamic function through blood flow measurements. In vitro and in silico models are also discussed. For gastrointestinal function, methods described include assessing gastric emptying and intestinal motility using in vitro tissue/organ baths and in vivo animal models, measuring gastric secretion in cell preparations and ligated rats, modeling nausea and emesis in ferrets and dogs, and measuring absorption in Caco-2 cell cultures and perfused intestinal segments of rats.
The document outlines the studies needed for an Investigational New Drug (IND) submission to the FDA. An IND application must contain information on animal pharmacology and toxicology studies, chemistry and manufacturing, and clinical protocols. It provides a flow chart showing the various preclinical studies required, including chemical and physical properties, biological studies, pharmacology, toxicology, and formulation studies. The goal of the preclinical studies is to generate data for the safety assessment of the new drug in humans.
Toxicokinetic evaluation in preclinical studies.pptxashharnomani
Toxicokinetic studies aim to understand what the body does with a drug at high doses. Such studies measure parameters like maximum plasma concentration, time to maximum concentration, and area under the plasma concentration curve. Toxicokinetic data from preclinical studies can be used to select appropriate doses and dosing routes for clinical trials and to interpret toxicity findings. Factors like protein binding, metabolism, and species differences must be considered when evaluating toxicokinetic data.
The document describes the hERG assay, which is used to test for potential drug-induced prolongation of the QT interval. It discusses the hERG gene and potassium channel, how mutations can cause long QT syndrome. It then summarizes three methods for conducting the hERG assay: electrophysiological assay using whole-cell patch clamping, Fluorometric imaging plate reader-based thallium flux assay, and radioligand binding with 35S-MK-499. Details are provided on cell preparation and protocol for each type of hERG assay.
Alternative methods to animals testing are the development and implementation of test method that avoid use of live animals or use of less animals in method.
The council directive on protection of animals used for experiments and scientific purpose in article 23
“The commission and member states should encourage
research into development and validation of alternative methods which could provide the same level of information as that obtained in experiment using animals but which involves less animal”.
Alternative methods able to do:
Reduce Refine Replace
collectively called as “The 3Rs Principle”.
Needs for alternative methods
Because in laboratory animals may be:
Poisoned.
Deprived of food water and sleep.
Applied with skin and eye irritants.
Subjected to psychological stress.
Deliberately infected with the infected disease.
Safety pharmacology studies are conducted to help protect clinical trial participants and patients from potential adverse effects of pharmaceuticals. The objectives are to adopt a rational approach in study design and conduct based on a drug's properties and intended uses. Safety pharmacology focuses on detecting undesirable pharmacodynamic effects of new drugs on physiological functions like the central nervous, cardiovascular and respiratory systems. Studies are generally conducted using relevant animal models or test systems to derive scientifically valid information. Results inform subsequent toxicology, kinetics and clinical studies.
IND (Investigational New Drug) industrial perspectiveAYESHA NAZEER
Describing the Industry's/sponsor's/drug manufacturers' perspective of the Investigational New Drug Application (IND) program based on the survey conducted by the Office Of Inspector General (OIG).
Herg assay,Structure, Various screening methods and AdvantagesUrvashi Shakarwal
The document discusses hERG assays, which are used to screen for compounds that may block the hERG potassium channel and prolong the heart's QT interval, potentially causing fatal arrhythmias. It describes the structure and function of the hERG channel, then summarizes various screening methods for hERG activity including electrophysiology, flux assays, fluorescence-based assays, and radioligand binding assays. These methods allow high-throughput screening of large numbers of compounds early in drug development to improve cardiovascular safety.
chronic dermal and inhalational studies as per OECDSohil Shah
This document presents guidelines for chronic toxicity studies as outlined by the OECD. It discusses the objectives of chronic toxicity studies which are to identify hazardous properties, target organs, dose responses, and predict chronic effects in humans. It describes principles such as administering test substances daily to rodents for 12 months to observe toxicity. It provides details on housing, feeding conditions, procedures, observations, and reporting of results for chronic dermal and inhalation studies.
The document provides an overview of the regulatory process for bringing a new drug to market, beginning with pre-clinical studies and submission of an Investigational New Drug (IND) application to the FDA. If approved, the IND allows clinical trials to be conducted in three phases to evaluate safety and efficacy. If phase 3 trials demonstrate a drug is safe and effective, a New Drug Application or Biologics License Application can be submitted for approval to market the drug. Ongoing monitoring of safety continues even after approval.
The document discusses the Investigational New Drug (IND) application process with the FDA. An IND application allows a company to ship an experimental drug across state lines and begin clinical trials. It must include preclinical data to show the drug is safe for initial human use as well as protocols for proposed studies. The FDA reviews the IND for 30 days before clinical trials may begin to ensure subject safety. The overall goal of an IND is to facilitate testing of new drugs while protecting clinical trial participants.
Alternative methods to animal toxicity testingSachin Sharma
This document presents information on alternative methods to animal toxicity testing. It discusses the need for alternatives due to the harms animals face in toxicity testing. The 3Rs principles of reduction, refinement and replacement are explained, which aim to minimize animal use and suffering. The validation process for new alternative methods through organizations like ECVAM is covered. Specific alternative methods mentioned include in vitro tests like the Ames test and HET-CAM test, in silico methods, and mathematical models. The HET-CAM test for eye irritation is described in more detail.
Toxicokinetic evaluation in preclinical studies by Shivam Diwaker Shivam Diwaker
Toxicokinetics evaluation in preclinical studies was presented. The presentation covered absorption, distribution, biotransformation and excretion of chemicals. Key points included how toxicokinetics quantifies exposure through measures like volume of distribution and clearance. The importance of evaluating metabolites and the factors influencing distribution and metabolism were discussed. Toxicokinetic studies are conducted at various stages of preclinical and clinical development to interpret toxicity results and support human trials. Alternative approaches to decrease animal usage in toxicokinetics were also presented.
Aris G is a leading pharmacovigilance system that enables companies to reduce safety risks for drugs, devices, vaccines and combination products. It improves case processing workflows and integrates with other systems. Vigi Flow is an ICSR management system developed by UMC that allows entry, assessment, storage and transmission of safety reports in accordance with ICH E2B standards. Both systems provide features for adverse event reporting, but Vigi Flow is web-based while Aris G can be installed locally.
OECD principles of Good laboratory practice. this ppt include the basic and necessary information required for OECD GLP guideline . Content is taken from official site
This document provides guidelines for safety pharmacology studies for human pharmaceuticals. It defines safety pharmacology as studies investigating potential undesirable pharmacological effects on physiological functions. The guidelines describe a core battery of studies on the central nervous, cardiovascular and respiratory systems to be conducted prior to first human administration. Follow up and supplemental studies may be warranted based on properties, class effects or safety concerns. The timing of studies in relation to clinical development is outlined.
Safety pharmacology studies investigate potential undesirable effects of new drugs on physiological functions like the central nervous, cardiovascular, and respiratory systems. The objectives are to protect clinical trial participants and patients from adverse effects. Core battery studies evaluate effects on vital organ systems, while follow-up studies provide more depth. Supplemental studies explore other organ systems if a cause for concern exists. Timing of studies is before and during clinical development. Studies may be reduced or eliminated based on product characteristics or information from toxicology.
safety pharmacology is the branch of pharmacology specializing in detecting and investigating potential undesirable pharmacodynamic effects of a new chemical on physiological functions .
the content of this presentation is as follows
- introduction
- definition
- history
- ICH - guidelines
- refrences
Safety pharmacology studies in drug developmentAnkita
In the given ppt we get idea about safety pharmacology studies. learn why safety pharmacology is important. concept of safety pharmacology, also get the knowledge from where safety pharmacology is originated
Safety pharmacology aims to identify adverse effects of drugs prior to clinical trials through guidelines established by the ICH. The antihistamine terfenadine was found to cause a rare but lethal cardiac effect and highlighted the need for improved preclinical safety testing. Safety pharmacology studies objectives are to detect undesirable pharmacodynamic properties and adverse effects observed in toxicology and help inform decisions about beginning human testing. A variety of in vitro and ex vivo methods are recommended including isolated tissue and cell-based assays, and zebrafish and stem cell models to comprehensively evaluate a new drug's safety profile.
This guideline was 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. This guideline provides a definition, general principles and recommendations for safety pharmacology studies
This document outlines guidelines for safety pharmacology studies. It defines safety pharmacology as evaluating undesirable pharmacodynamic properties that may impact human safety. The objectives are to identify potential adverse effects and investigate mechanisms. The guidelines provide recommendations on study design, test systems, dose levels, duration and core battery assessments of cardiovascular, respiratory and central nervous systems. Follow-up studies may further explore areas of concern identified. Application of good laboratory practice depends on the study purpose and potential implications for safety. The overall aim is to rationally assess pharmaceuticals and protect clinical trial and marketed product users from adverse effects.
Introduction to drug discovery and development.pptxMingmaLhamuBhutia
The document provides an overview of drug discovery and development. It discusses the various stages including discovery, preclinical research, clinical trials (phases 1-4), regulatory approval, and post-approval surveillance. The discovery stage involves identifying drug targets and lead compounds. Preclinical research involves safety testing in animals. Clinical trials test safety and efficacy in humans in phases. Regulatory agencies approve drugs that are proven safe and effective. Post-approval surveillance monitors drugs after market release. The overall process aims to develop innovative therapies while ensuring patient safety.
Preclinical trials involve testing new drugs and medical devices on animals before human testing to assess safety and efficacy. They include various studies such as screening tests, isolated organ tests, and toxicity tests on rodents and larger animals. The goals are to determine dosing, identify adverse effects, and collect sufficient safety data to file for approval to begin clinical trials in humans under good laboratory practices. Preclinical studies help establish that initial human trials can reasonably proceed safely.
Pre-clinical drug development involves several key stages: high throughput screening to identify potential drug candidates, toxicology studies in animal models to determine safety, pharmacological profiling to understand mechanisms of action, and calculating initial human doses. The overall goals are to obtain sufficient data on safety, tolerability and efficacy to receive regulatory approval from the FDA to begin clinical trials in humans. Pre-clinical studies provide critical data required for an Investigational New Drug (IND) application to the FDA.
ich guidelines for clinical trials, scientific approach ppt.pptxJyotshnaDevi4
The document outlines the ICH guidelines for conducting clinical trials. It describes the objectives to promote common understanding and evaluation of foreign clinical trial data. Clinical trials should follow scientific principles and protect subjects. Trials generally proceed through four phases, starting with small healthy volunteer studies (Phase I) to evaluate safety, followed by exploratory efficacy studies (Phase II), then confirmatory efficacy and dosing studies (Phase III), and finally post-marketing studies (Phase IV). Special populations like children, pregnant women, and those with organ impairment require unique consideration. Proper study design, conduct, analysis and reporting are emphasized.
Phase 1 clinical trials involve first administering an experimental drug to humans to evaluate its safety, determine a safe dosage range, and identify potential side effects. These early-stage trials typically involve small groups of 20-80 healthy volunteers or patients and can last 3-6 months. The primary goal is to establish a maximum tolerated dose and safe dosage for later phase trials to further evaluate effectiveness. Tests are conducted at regular intervals to monitor the drug's effects on major organ systems and establish pharmacokinetic properties like blood concentration levels over time. Around 70% of experimental drugs successfully pass phase 1 trials.
This document provides guidelines for safety pharmacology and toxicology studies for pharmaceutical products. It outlines the objectives and types of studies recommended at different stages of clinical development, including safety pharmacology core battery studies, follow-up studies, reproductive and developmental toxicity studies, and human studies. Test systems, dose levels, durations, endpoints, and good laboratory practice standards are discussed for each type of nonclinical study.
This document discusses the process of new drug evaluation, which involves 3 phases - drug discovery, preclinical testing, and clinical trials. In the drug discovery phase, candidate molecules are selected. Preclinical testing involves animal studies to evaluate safety. Clinical trials with human subjects are then conducted in 3 phases to evaluate efficacy, safety, and adverse effects. The clinical trials process is highly regulated to ensure safety and data integrity. If successful, a New Drug Application is filed with regulatory authorities for approval to market the new drug.
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
This document provides an overview of the regulatory guidelines for developing and marketing biologics in Europe. It discusses the EU guidelines for non-clinical and clinical studies from trials through approval. For non-clinical studies, the CHMP has adopted ICH S6 and its addendum which provides guidance on species selection, study design, immunogenicity, reproductive/developmental toxicity, and carcinogenicity assessments. Clinical studies must comply with the Clinical Trials Directive and guidelines on GCP, informed consent, data handling and confidentiality. The marketing authorization application process is similar to other products but requires additional information specific to biologics manufacturing.
Preparation of Clinical Trial Protocol of India.Aakashdeep Raval
The document provides information on clinical trial protocols in India. It discusses the purpose of clinical trials and phases of clinical trials from Phase 0 to Phase 4. It explains that the clinical trial protocol is a document that states the background, objectives, design, methodology and statistical considerations of a clinical trial. The protocol describes inclusion/exclusion criteria, assessments of efficacy and safety, data management, quality control and other key elements to ensure proper conduct of the clinical trial. An effective clinical trial protocol provides all the necessary details to guide researchers in safely and ethically evaluating a medical treatment.
Phase 1 clinical trials are the first studies done in humans of a new drug or treatment. They aim to determine the drug's safety and side effects, identify the maximum tolerated dose, and understand how the body processes the drug through pharmacokinetic evaluation. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent clinical trial phases that further evaluate efficacy.
This document outlines objectives and principles of safety pharmacology studies. It discusses using such studies to protect clinical trial participants from potential adverse drug effects. The document describes the scope of safety pharmacology, considerations for test systems and study design, and examples of core safety pharmacology assessments of the central nervous, cardiovascular and respiratory systems. Evaluation methods are also summarized for each system. The document concludes by listing some references on safety pharmacology guidelines.
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1. Clinical Research And Pharmacovigilance
“Safety Pharmacology”
by
Chetan A., M.Pharm 1st Year (Pharmacology)
K.K. College of Pharmacy
Chennai, TamilNadu
2. Learning Objective
• Introduction
• Safety Pharmacology
• General Considerations in Selection & Design of Study
• General Consideration on Test Systems:
• Safety Pharmacology Studies
• Guidelines
• Conditions under which Safety Pharmacology Studies are not necessary
• Pre-clinical Safety Pharmacology
• Conclusion
• Recent Research
• Reference
3. Pharmacology
Pharmacology is the branch of pharmaceutical sciences which is concerned with
the study of drug action on body.
• Types of Pharmacology
• Primary Pharmacology - Effects of a substance in relation to its desired therapeutic
target (Mechanism of Action; MOA).
• Secondary Pharmacology - Identifying/understanding “off-target effects”. Effects
of a substance not related to its desired therapeutic target
• Safety Pharmacology - Investigates the potential undesirable pharmacodynamic
effects of a substance on physiological functions in relation to exposure in the
therapeutic range and above.
5. Safety Pharmacology
• Safety pharmacology is a branch of pharmacology specialising in
detecting and investigating potential undesirable pharmacodynamic
effects of new chemical entities (NCEs) on physiological functions in
relation to exposure in the therapeutic range and above.
• 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.
• These test are conducted at doses not too much in excess of the intended
clinical dose.
6. General Principle
• Rational approach in Design and Conduct based on
Pharmaceutical’s Properties and uses.
• Scientifically valid methods to be used.
• Use of new technologies and methodologies is encouraged.
• Safety pharmacology end points can be incorporate in design of
Toxicology, kinetics, clinical studies etc.
7. Key Aim 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
8. Objectives of Safety Pharmacology
• HAZARD IDENTIFICATION
To identify undesirable pharmacodynamic properties of a
substance that may have relevance to its human safety
• RISKASSESSMENT
To evaluate adverse pharmacodynamic or pathophysiological
effects of a substance observed in toxicology studies
• RISK MANAGEMENT/MITIGATION
To investigate the mechanism of the adverse pharmacodynamic
effects observed
9. Key Issues
• The following key issues have to be considered within safety
pharmacology:
• 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 (risk management)
10. General Considerations in Selection & Design of Study
• 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 .
11. Continuation.,,
• 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.
12. Continuation..,
• 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 .
13. Test System
• General Consideration on 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.
• Data from humans (e.g., in vitro metabolism), when available, should
also be considered.
• The time points for the measurements should be based on
pharmacodynamic and pharmacokinetic consideration
• Justification should be provided for the selection of the particular animal
model or test system.
14. Use of In Vivo and In Vitro Studies
• Animal Models as well as ex vivo and in vivo preparations can be used as test
systems.
• Ex vivo and in vivo systems can include:
a) Isolated organs & tissues
b) Cell Culture
c) Cell Organelles
d) Subculture Organelles etc
• In vivo animal study include,
a) Use of unanaesthetized animals
b) Data from unrestrained animals used for telemetry
c) For unanesthetized animals, the avoidance of discomfort or pain is a foremost
consideration
15. Experimental Design
• Sample size and use of controls
a) Size of the group should be sufficient to allow meaningful scientific interpretation.
b) No. of animals should be adequate
c) Negative and Positive control groups should be included.
d) In vivo System - positive group may not be necessary.
e) Exclusion of controls from subject should be justified.
• Route of Administration:
a) Clinical route of administration should be used
b) Exposure to the parent substance and its metabolites should be similar to that
achieved in humans
c) If clinical use involves multiple routes, consider more than one route.
16. Dose levels or Concentrations of Test Substances
• In Vivo Studies:
a) It should be designed to define the dose-response relationship of the adverse effects
observed.
b) The dose elicting the adverse effect should be compared to the doses elicting the
primary pharmacodynamic effect in the test species or the proposed therapeutic
effect in humans, feasible.
c) It is recognized that there are species differences in pharmacodynamic sensitivity.
Therefore, should include and exceed the primary pharmacodynamic or therapeutic
range.
d) In the absence of an adverse effect, the highest tested dose should be a dose that
produces moderate adverse effects in this or in other studies of similar route &
duration. These adverse effects can include dose-limiting pharmacodynamics effects
or toxicity.
17. Continuation..,
• Testing of a single group at the limiting dose as described above may be
sufficient in the absense of an adverse effect on safety pharmacology
endpoints in the test species.
• In Vitro Studies
a) It should be deesigned to establish a concentration-effect relationship.
b) The range of concentration used should be selected to increase the likelihood
of detecting an effect on the test system.
c) The upper limit of this range may be influenced by physio-chemical
properties of the test substance and other assay specific factors.
d) In the absence of an effect, the range of concentration selected should be
justified.
18. Timing of Safety Pharmacology Studies in Relation to
Clinical Development
• Conducted prior to Administration in Humans (First in Huaman
[FIH];Investigational New Drug [IND] application, “IND-enabling”)
• During Clinical Development (Clinical Trials Phases 1-3)
• Before Approval (NDA application)
• Post-approval safety pharmacology investigations
20. Duration of Studies
• Are generally performed in Single dose administration
• The duration of the safety pharmacology studeis to address the following
effects should be rationally based on,
1. When pharmacodynamic effects occur only after a certain duration of
treatment
2. When results from repeat dose non-clinical studies
3. Results from use in humans give rise to concerns about safety
pharmacological effects.
22. Safety Pharmacology Studies
I. Safety Pharmacology Core Battery
• Safety pharmacology core battery is to investigate the effects of the test
substance on vital functions.
a) Follow-up Studies For Safety Pharmacology Core Battery
These are meant to provide a greater depth of understanding than, or
additional knowledge to, that provided by the core battery on vital functions for
potential adverse pharmacodynamic effects
II. Supplemental Safety Pharmacology Studies
• To evaluate potential adverse pharmacodynamic effects on organ system
functions not addressed by the core battery or repeated dose toxicity studies
23. I. Safety Pharmacology Core Battery
• Tier 1
1. Central Nervous System
2. Cardiovascular System
3. Respiratory System
1. Central Nervous System
In Core battery
• Motor activity
• Behavioral changes
• Coordination
• Sensory/motor reflex response
• Body Temperature
In Follow-up studies
• Learning and memory
• Ligand-specific binding
• Neurochemistry
• Visual & auditory examination
24. 1. Central Nervous System
• Evaluation Methods
1. Functional Observation Battery (FOB)
2. Irwin’s test
FOB method of evaluation involves Neurological and
Neuropathological investigations
25. Irwin’s Test
• This method is to evaluate the qualitative effect of test substance on behavioural and
physiological functions and also duration of action
• The parameters observed are,
AUTONOMIC
EFFECTS
SENSORIMOTOR
EFFECTS
NEUROMUSCULAR
EFFECTS
BEHAVIOURAL
EFFECTS
Salivation Touch response Posture Arousal
Lacrimisation Palpebral reflex Grip strength Vocalisation
Pilorection Startle reflex Tremor Aggressiveness
Rectal temperature Pinna reflex Traction response Sniffing
Abnormal urination,
defecation, respiration
Writhing reflex Twitches Grooming
26. Continuation..,
Conclusion
• This test provide a rapid detection of test substances toxicity, active
dosage range Effects on behavioural and physiological function
Modification:
• Functional Observation Battery(FOB)
27. 1. Central Nervous System
• Other evaluation techniques
1. Rotarod
2. Hot plate test, Tail flick, paw pressure
3. Photoelectric beam interruption techniques
4. Passive avoidance tests
5. Pentylenetetrazol (PTZ) seizure tests
6. Electroencephalography (EEG)
• Emerging Techniques
1. Automated video systems
2. Integrated video and EEG systems
28. 2. Cardiovascular Systems (CVS)
Core Battery
• Blood Pressure
• Heart rate
Follow up Studies
• Cardiac output
• Ventricular contractility
• Vascular resistance
• Endogeneous & Exogeneous
substances on the Cardiovascular response
30. hERG assay (human Ether-a-go-go Related Gene)
• The alpha subunit of a potassium ion channels in the heart that codes for
a protein known as Kv11.1
• Ion channel proteins (the ‘rapid’ delayed rectifier current (IKr)) that
conducts potassium (K+) ions out of the muscle cells of the heart.
• Inhibition of the hERG current causes QT interval prolongation resulting
in potentially fatal ventricular tachyarrythmia called Torsade de Pointes
32. 3. Respiratory System
1. Plethysmography
2. Head out Plethysmography
3. Whole body Plethysmography
• Respiratory parameters:
1. Insoiratoey Time (Ti, ms)
2. Expiratory Time (Te, ms)
3. Peak Inspiratiory Flow (PIF, ml/s)
4. Tidal Volume (TV, ml)
5. Respiratory Rate (ResR, breaths/min)
6. Relaxation Time (Tr, ms)
33. II. Supplement Safety Pharmacology Studies
• Tier 2
1. Renal/Urinary System
2. Gastrointestinal System
3. Other organs - Skeletal System, Immune & Endocrine functions
1. Renal/Urinary System
Renal parameters should be assessed are
a) Urinary volume
b) Specific gravity
c) Osmolarity
d) pH, fluid/electrolyte balance
e) Proteins, cytology &
f) Blood chemistry determinations such as blood urea nitrogen, Na+, Cl-, K+, creatinine
and plasma proteins
34.
35. 2. Gastrointestinal System
• Gastric secretion
• Gastrointestinal injury potential
• Bile secretion
• Transit time in vivo
• Ileal contraction in vivo
• Gastric pH measurement
• Gastric emptying
• Intestinal motility
• Emesis induction
36. 2. Gastrointestinal System
• Evaluaion Methods
a) Barium sulphate (BaSO4) or a charcoal test meal
b) Pylorus ligation test
• Emerging techniques
a) Endoscopy
b) Biomarkers
c) EMG Citrulline
d) miR-194
e) Calprotectin
37. Alternative Methods
• Zebrafish model: Anticonvulsant activity, locomotor activity,
behavioural paradigms such as addiction, memory and anxiety.
• human Embryonic Stemcell derived Cardiomyocytes (hESC-CM)
and human inducible Pluriopotent Stemcell derived Cardiomyocytes
(hiPS-CM) as models of in vitro high throughput drug screening and
CVS safety assessment.
39. Objectives of the Guideline
• To help protect clinical trial participants and patients receiving
marketed products from potential adverse effects of
pharmaceuticals
• Avoiding unnecessary use of animals and other resources
40. Guidlines
• Safety pharmacology studies are described in ICH guidances
• ICH S7A outlines the core battery studies and discusses the supplemental
studies
• ICH S7B details the procedures for conducting an in vitro evaluation of
delayed ventricular prolongation (QT interval prolongation)
• All safety pharmacology must be conducted in accordance with these
guidances
41. Conditions under which Safety Pharmacology Studies are
not necessary
• Safety pharmacology studies are usually not required for locally
applied agents eg, Dermal or Ocular, in cases when the
pharmacology of the investigational drug is well known, and/or
when systemic absorption from the site of application is low.
• Safety pharmacology testing is also not necessary, in the case of
a new derivative having similar pharmacokinetics and
pharmacodynamics.
42. Country-Specific Highlights: INDIA
• Agency: Central Drugs Standard Control Organization
• Website: http://www.cdsco.nic.in/
• Has specific guidelines for drug/vaccine development
• Drugs and Cosmetics (IIND Amendment) Rules “Schedule Y”
(2005) – Treats vaccine like a small molecule and requires
studies in two species, and requires both single-dose and repeat-
dose toxicity studies
43. Preclinical safety pharmacology
• Preclinical safety pharmacology integrates in silico, in vitro and in vivo
approaches.
• 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.
44. Conclusion
• In summary, safety pharmacology is a discipline that plays an important
role in protecting human volunteers and patients from a new compound’s
potential for undesirable pharmacodynamic effects.
• Safety pharmacology studies evaluate nervous system, cardiovascular
and respiratory functionover a range of doses in the therapeutic range
and above that do not cause overt toxicity.
• Safety pharmacology is a diverse and exciting field that offers careers in
a number of different areas such as academia, industry and regulatory
agencies.
45. Recent Research
Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivocanine models
- Kentaro Ando et,al. (2020)
Cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly
increasing number of cancer survivors. “onco-cardiology” or “cardio-oncology” is a new discipline for
addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase
inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic
breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including Qt-interval
prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new
method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, they
intravenously administered lapatinib to halothane-anaesthetised dogs, evaluating cardiohemodynamic,
electrophysiological, and echocardiographic profiles for pharmacological safety assessments. They
intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic
potential. the therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance,
QT, QTc, monophasic action potential (MAp)90(sinus), MAp90(CL400), effective refractory period, and
plasma concentration of cardiac troponin i (ctni), suggesting that lapatinib prolonged the ventricular
repolarization without inducing lethal ventricular arrhythmia. careful monitoring of plasma ctni concentration
and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced
cardiovascular adverse events.