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.
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.
clinical and preclinical approaches to drug discovery.Here we mainly deals with preclinical approaches, ie. Pharmacological approach and toxicological approach
Toxicological Approach to Drug DiscoverySuhas Reddy C
This document outlines the toxicological approach to drug development. It discusses the importance of conducting various toxicity studies at different stages of drug development to ensure safety. These include single dose, repeated dose, fertility, reproductive, developmental and genotoxicity studies in animals. It describes the typical safety program involving staged approach and discusses factors to consider in designing toxicity studies. The goal is to obtain sufficient non-clinical safety data to support clinical trials and assess safety for human use.
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
The document discusses extrapolating data from preclinical in vitro and in vivo animal studies to humans in clinical trials. It provides information on different types of studies and explains how data from animal models is used to estimate safe starting doses for human subjects. The key points are:
1) Preclinical studies test drugs in animal and cell models before human trials to evaluate toxicity and effects. Data from these studies is extrapolated using mathematical processes to estimate appropriate human doses.
2) The no-observed-adverse-effect level (NOAEL) from animal studies is used to calculate a human equivalent dose (HED) based on body surface area, accounting for differences between species.
3) Additional safety factors are applied
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.
Toxicokinetics deals with absorption , distribution , biotransformation and excretion of chemicals .
According to ICH S3A guidance on the assessment of systemic exposure in toxicity studies , toxicokinetics is defined as the generation of pharmacokinetics data , either as an integral component in the conduct of non-clinical toxicity studies or in specially designed supportive studies , in order to assess systemic exposure.
Toxicokinetics is the science to understand what the body does with a drug when the drug is given at a relatively high dose . Toxicokinetics play a major role in interpreting the histopathological finding in a toxicological study.
Toxicokinetic is essentially the study of "how a substance gets into the body and what happens to it in the body."
The primary objective of toxicokinetic is:
• To describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study.
Secondary objectives are:
• To relate the exposure achieved in toxicity studies to toxicological findings and
contribute to the assessment of the relevance of these findings to clinical safety.
• To support the choice of species and treatment regimen in non-clinical toxicity studies.
• To provide information which, in conjunction with the toxicity findings, contributes to the design of subsequent non-clinical toxicity studies.
The primary purpose of toxicokinetic studies is to determine the rate, extent and duration of systemic exposure of the test animal species to the test compound at the different dose levels employed during toxicity studies and to provide data for direct comparison with human exposure to the test compound.
These data help to understand the relationship between observed toxicity and administered dose. They also play a role in the clinical setting, assisting in the setting of plasma limits for early human exposure and in the calculation of safety margins.
A major challenge in the risk/benefit assessment of new chemical entities is the rational and reliable extrapolation of preclinical (nonclinical) safety evaluation data from animals to humans.
Toxicity studies, core to the safety evaluation process, are designed to determine a no observed toxic effect level as well as an observed toxic effect level.
Traditionally, these levels have been those of administered dose, and safety margins are derived as the ratio between the preclinical no observed toxic effect dose level in animals and the clinical (or environmental) dose level in humans.
In reality, however, safety margins thus derived are often optimistic guesses because they do not take into account the respective systemic exposures to the test compound during the preclinical studies and eventual human clinical (or environmental) use.
Toxicokinetics involves the generation of kinetic data to assess systemic exposure, either as an integral component of preclinical toxicity studies, or in specially designed supportive 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.
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.
clinical and preclinical approaches to drug discovery.Here we mainly deals with preclinical approaches, ie. Pharmacological approach and toxicological approach
Toxicological Approach to Drug DiscoverySuhas Reddy C
This document outlines the toxicological approach to drug development. It discusses the importance of conducting various toxicity studies at different stages of drug development to ensure safety. These include single dose, repeated dose, fertility, reproductive, developmental and genotoxicity studies in animals. It describes the typical safety program involving staged approach and discusses factors to consider in designing toxicity studies. The goal is to obtain sufficient non-clinical safety data to support clinical trials and assess safety for human use.
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
The document discusses extrapolating data from preclinical in vitro and in vivo animal studies to humans in clinical trials. It provides information on different types of studies and explains how data from animal models is used to estimate safe starting doses for human subjects. The key points are:
1) Preclinical studies test drugs in animal and cell models before human trials to evaluate toxicity and effects. Data from these studies is extrapolated using mathematical processes to estimate appropriate human doses.
2) The no-observed-adverse-effect level (NOAEL) from animal studies is used to calculate a human equivalent dose (HED) based on body surface area, accounting for differences between species.
3) Additional safety factors are applied
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.
Toxicokinetics deals with absorption , distribution , biotransformation and excretion of chemicals .
According to ICH S3A guidance on the assessment of systemic exposure in toxicity studies , toxicokinetics is defined as the generation of pharmacokinetics data , either as an integral component in the conduct of non-clinical toxicity studies or in specially designed supportive studies , in order to assess systemic exposure.
Toxicokinetics is the science to understand what the body does with a drug when the drug is given at a relatively high dose . Toxicokinetics play a major role in interpreting the histopathological finding in a toxicological study.
Toxicokinetic is essentially the study of "how a substance gets into the body and what happens to it in the body."
The primary objective of toxicokinetic is:
• To describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study.
Secondary objectives are:
• To relate the exposure achieved in toxicity studies to toxicological findings and
contribute to the assessment of the relevance of these findings to clinical safety.
• To support the choice of species and treatment regimen in non-clinical toxicity studies.
• To provide information which, in conjunction with the toxicity findings, contributes to the design of subsequent non-clinical toxicity studies.
The primary purpose of toxicokinetic studies is to determine the rate, extent and duration of systemic exposure of the test animal species to the test compound at the different dose levels employed during toxicity studies and to provide data for direct comparison with human exposure to the test compound.
These data help to understand the relationship between observed toxicity and administered dose. They also play a role in the clinical setting, assisting in the setting of plasma limits for early human exposure and in the calculation of safety margins.
A major challenge in the risk/benefit assessment of new chemical entities is the rational and reliable extrapolation of preclinical (nonclinical) safety evaluation data from animals to humans.
Toxicity studies, core to the safety evaluation process, are designed to determine a no observed toxic effect level as well as an observed toxic effect level.
Traditionally, these levels have been those of administered dose, and safety margins are derived as the ratio between the preclinical no observed toxic effect dose level in animals and the clinical (or environmental) dose level in humans.
In reality, however, safety margins thus derived are often optimistic guesses because they do not take into account the respective systemic exposures to the test compound during the preclinical studies and eventual human clinical (or environmental) use.
Toxicokinetics involves the generation of kinetic data to assess systemic exposure, either as an integral component of preclinical toxicity studies, or in specially designed supportive studies.
This document outlines the principles and types of non-clinical toxicity studies conducted in animals prior to testing pharmaceuticals in humans. It discusses general principles like complying with Good Laboratory Practice, using standardized equipment and protocols. It also describes the different types of toxicology studies including toxicokinetic, reproductive toxicity, teratogenicity and perinatal studies. The goal is to assess safety and predict potential adverse effects in humans by administering test substances to animals and observing toxicity.
S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES
S3B: PHARMACOKINETICS: GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIES
A well designed toxicokinetic study may involve several different strategies and depends on the scientific question to be answered. Controlled acute and repeated toxicokinetic animal studies are useful to identify a chemical's biological persistence, tissue and whole body half-life, and its potential to bioaccumulate. Toxicokinetic profiles can change with increasing exposure duration or dose. Real world environmental exposures generally occur as low level mixtures, such as from air, water, food, or tobacco products. Mixture effects may differ from individual chemical toxicokinetic profiles because of chemical interactions, synergistic, or competitive processes. For other reasons, it is equally important to characterize the toxicokinetics of individual chemicals constituents found in mixtures as information on behavior or fate of the individual chemical can help explain environmental, human, and wildlife biomonitoring studies.
ICH guidelines provide standards for toxicity studies to ensure safe, effective, and high quality pharmaceutical products. Guideline S3A deals with conducting toxicity studies and quantifying exposure. General principles include quantifying exposure levels in different species and sexes using plasma concentration or area under the curve. Toxicokinetic studies should be performed to determine metabolite levels and justify dose levels. Reporting should include detailed toxicokinetic data and evaluation. Toxicokinetics are assessed in various toxicity studies including single dose studies, repeated dose studies, genotoxicity studies, carcinogenicity studies, and reproductive toxicity studies.
This document discusses experimental approaches for carcinogenicity testing. It provides guidance on conducting carcinogenicity studies, including factors to consider like drug candidates, cause for concern, genotoxicity, experimental design, and guidelines for conducting studies such as species and strain selection, group size, duration, dose selection, and routes of administration. The goal is to identify potential carcinogenic risks of drugs in animals and humans.
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.
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.
Preclinical Toxicity Studies-Tool of Drug Discoverydynajolly
As per WHO “Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient”. Hence the prime objective of using any substance as a drug is that it must be beneficial for the humans. A large number of compounds are synthesized every year but they cannot be directly used in humans as drugs because no one knows or can predict the possible harmful effects of these compounds in humans. That is why to explore the complete pharmacological profile of these compounds and to ensure complete human safety they are first tested on animals before clinical use. Preclinical Studies thus can be defined as “Testing the newly discovered compound in animals with the objective of gaining information regarding the various aspects of the compound with respect to the biological systems so that the same can be extrapolated for the use of that compound in humans”. As the evaluation progresses undesirable compounds gets rejected at each step, so that only a few out of thousands reach the stage when administration to the humans is considered.
Pharmacovigilance and Pharmacoepidemiology journal accepts articles from different disciplines as below but not constrained to only these Pharmacovigilance signal, Pharmacovigilance data management, Design and development of drug, Principles of pharmacology, Quality system and pharmacovigilance, Pharmacovigilance softwares, Drug regulatory activities, Drug reactions and diagnosis, Reporting systems, Clinical trials and pharmacovigilance, Marketing surveillance, Pharmacovigilance ethics and regulations, Biomarkers and pharmacology , Concepts and trends in pharmacovigilance, Pharmaceutical medicines, Drug delivery systems, Statistics and data management.
Ich (s5 r2) The International Council for Harmonisationof Technical Requireme...AMIT KUMAR
GUIDLINES FOR REPRODUCTIVE TOXICOLOGY,Strategies for reproductive toxicity assessment,The International Council for Harmonisation,of Technical Requirements for Pharmaceuticals for Human Use
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
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.
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
This document summarizes information about toxicokinetics and saturation kinetics studies presented by Shilajit Das. It discusses how toxicokinetics studies are used to evaluate systemic drug exposure in animals and relate it to dose levels and toxicity findings to assess human safety. It provides the objectives, goals and general principles of toxicokinetics studies including quantifying exposure, justifying sampling timepoints, and determining metabolites. It also discusses how saturation kinetics can cause non-linear pharmacokinetics when enzyme or carrier capacities are exceeded, and how this non-linearity can be detected by evaluating parameters like bioavailability and clearance at different doses.
Toxicity studies in animals are conducted to identify any toxic effects of a substance prior to clinical use in humans. The document outlines various types of toxicity studies including acute, subacute, chronic, and lethality studies. Acute studies involve a single high dose to determine toxic effects over 14 days, while repeated dose studies like subacute and chronic studies administer multiple lower doses over weeks to years to identify target organ toxicity. Lethality studies determine the lethal dose for 50% of animals (LD50). Systemic toxicity parameters evaluated include effects on liver, kidney, heart and other organs. Toxicity studies provide safety information required for approval to conduct human clinical trials.
Assignment on Toxicokinetics- Toxicokinetic evaluation in preclinical studies, saturation kinetics Importance and applications of toxicokinetic studies. Alternative methods to animal toxicity testing.
This document discusses various types of animal toxicity studies conducted prior to clinical use of drugs in humans. It provides objectives and details of reproductive and developmental toxicity studies, local toxicity studies, carcinogenicity studies, and genotoxicity studies. Reproductive toxicity studies examine effects on fertility and development in offspring. Developmental toxicity studies evaluate effects during pregnancy and across lifespan. Local toxicity studies are required when drugs are administered via non-oral routes. Carcinogenicity studies identify substances that may induce or increase tumors.
In vivo is the Latin word which means with in the living body.
When effects of various biological entities are tested on whole, living organism or cells, usually animals including humans and plants.
Animal testing and clinical trials are major elements of in-vivo research.
In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject in drug discovery.
example, verification of efficacy in vivo is crucial, because in vitro assays can sometimes yield misleading results with drug.
Harry Smith found that sterile filtrates of serum from animals infected with Bacillus anthracis were lethal for other animals, whereas extracts of culture fluid from the same organism grown in vitro were not.
In microbiology Once cells are disrupted and individual parts are tested or analyzed, this is known as in vitro.
In vitro studies within the glass, i.e., in a laboratory environment using test tubes, petri dishes, etc. Examples of investigations in vivo include: the pathogenesis of disease.
In vitro toxicology:-
The bridge exists between new drug discovery and drug development.-
Provide information on mechanism of action of a drug
Provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate or to proceed further.
In vitro methods are widely used for:-
Screening and ranking chemicals
Get a platform for animal studies for physiological actions
Studying cell, tissue, or target specific effects
Improve subsequent study design
Advantages and Disadvantages:-
Faster than in vivo studies
Less expensive to run
Less predictive of toxicity in intact organisms
In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or observations made in vitro to predict phenomena in vivo, biological organisms.
The problem of transposing in vitro results is particularly acute in areas such as toxicology where animal experiments are being phased out and are increasingly being replaced by alternative tests.
Results obtained from in vitro experiments cannot often be directly applied to predict biological responses of organisms to chemical exposure in vivo.
Therefore, it is extremely important to build a consistent and reliable in vitro to in vivo extrapolation method.
Two solutions are now commonly accepted:
Increasing the complexity of in vitro systems where multiple cells can interact with each other in order recapitulate cell-cell interactions present in tissues (as in "human on chip" systems).
Using mathematical modeling to numerically simulate the behavior of a complex system, whereby in vitro data provides the parameter values for developing a model.
The two approaches can be applied simultaneously allowing in vitro systems to provide adequate data for the development of mathematical models. To comply with push for the development of alternative testing methods.
Experimental Techniques For Evaluation Of New Drugs.pptKarabiAdak
Experimental techniques are used to evaluate new drugs for toxicity, efficacy, and safety prior to human clinical trials. This includes acute and chronic toxicity studies in two animal species to identify target organ toxicity and establish a maximum tolerated dose. Genotoxicity and carcinogenicity studies are also conducted to assess genetic damage and cancer risk. Alternative methods seek to reduce animal testing through computer models, cell cultures, and organ-specific assays.
This document discusses various toxicokinetic studies conducted in preclinical stages of drug development. It describes conducting single dose, rising dose, repeated dose toxicity studies in rodents and non-rodents to determine kinetic parameters and assess safety. The importance of toxicokinetic data in setting safe clinical doses is highlighted. Alternative methods to animal testing like in vitro, in silico, cell line techniques and patch clamp method are also summarized.
This document outlines the principles and types of non-clinical toxicity studies conducted in animals prior to testing pharmaceuticals in humans. It discusses general principles like complying with Good Laboratory Practice, using standardized equipment and protocols. It also describes the different types of toxicology studies including toxicokinetic, reproductive toxicity, teratogenicity and perinatal studies. The goal is to assess safety and predict potential adverse effects in humans by administering test substances to animals and observing toxicity.
S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES
S3B: PHARMACOKINETICS: GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIES
A well designed toxicokinetic study may involve several different strategies and depends on the scientific question to be answered. Controlled acute and repeated toxicokinetic animal studies are useful to identify a chemical's biological persistence, tissue and whole body half-life, and its potential to bioaccumulate. Toxicokinetic profiles can change with increasing exposure duration or dose. Real world environmental exposures generally occur as low level mixtures, such as from air, water, food, or tobacco products. Mixture effects may differ from individual chemical toxicokinetic profiles because of chemical interactions, synergistic, or competitive processes. For other reasons, it is equally important to characterize the toxicokinetics of individual chemicals constituents found in mixtures as information on behavior or fate of the individual chemical can help explain environmental, human, and wildlife biomonitoring studies.
ICH guidelines provide standards for toxicity studies to ensure safe, effective, and high quality pharmaceutical products. Guideline S3A deals with conducting toxicity studies and quantifying exposure. General principles include quantifying exposure levels in different species and sexes using plasma concentration or area under the curve. Toxicokinetic studies should be performed to determine metabolite levels and justify dose levels. Reporting should include detailed toxicokinetic data and evaluation. Toxicokinetics are assessed in various toxicity studies including single dose studies, repeated dose studies, genotoxicity studies, carcinogenicity studies, and reproductive toxicity studies.
This document discusses experimental approaches for carcinogenicity testing. It provides guidance on conducting carcinogenicity studies, including factors to consider like drug candidates, cause for concern, genotoxicity, experimental design, and guidelines for conducting studies such as species and strain selection, group size, duration, dose selection, and routes of administration. The goal is to identify potential carcinogenic risks of drugs in animals and humans.
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.
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.
Preclinical Toxicity Studies-Tool of Drug Discoverydynajolly
As per WHO “Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient”. Hence the prime objective of using any substance as a drug is that it must be beneficial for the humans. A large number of compounds are synthesized every year but they cannot be directly used in humans as drugs because no one knows or can predict the possible harmful effects of these compounds in humans. That is why to explore the complete pharmacological profile of these compounds and to ensure complete human safety they are first tested on animals before clinical use. Preclinical Studies thus can be defined as “Testing the newly discovered compound in animals with the objective of gaining information regarding the various aspects of the compound with respect to the biological systems so that the same can be extrapolated for the use of that compound in humans”. As the evaluation progresses undesirable compounds gets rejected at each step, so that only a few out of thousands reach the stage when administration to the humans is considered.
Pharmacovigilance and Pharmacoepidemiology journal accepts articles from different disciplines as below but not constrained to only these Pharmacovigilance signal, Pharmacovigilance data management, Design and development of drug, Principles of pharmacology, Quality system and pharmacovigilance, Pharmacovigilance softwares, Drug regulatory activities, Drug reactions and diagnosis, Reporting systems, Clinical trials and pharmacovigilance, Marketing surveillance, Pharmacovigilance ethics and regulations, Biomarkers and pharmacology , Concepts and trends in pharmacovigilance, Pharmaceutical medicines, Drug delivery systems, Statistics and data management.
Ich (s5 r2) The International Council for Harmonisationof Technical Requireme...AMIT KUMAR
GUIDLINES FOR REPRODUCTIVE TOXICOLOGY,Strategies for reproductive toxicity assessment,The International Council for Harmonisation,of Technical Requirements for Pharmaceuticals for Human Use
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
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.
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
This document summarizes information about toxicokinetics and saturation kinetics studies presented by Shilajit Das. It discusses how toxicokinetics studies are used to evaluate systemic drug exposure in animals and relate it to dose levels and toxicity findings to assess human safety. It provides the objectives, goals and general principles of toxicokinetics studies including quantifying exposure, justifying sampling timepoints, and determining metabolites. It also discusses how saturation kinetics can cause non-linear pharmacokinetics when enzyme or carrier capacities are exceeded, and how this non-linearity can be detected by evaluating parameters like bioavailability and clearance at different doses.
Toxicity studies in animals are conducted to identify any toxic effects of a substance prior to clinical use in humans. The document outlines various types of toxicity studies including acute, subacute, chronic, and lethality studies. Acute studies involve a single high dose to determine toxic effects over 14 days, while repeated dose studies like subacute and chronic studies administer multiple lower doses over weeks to years to identify target organ toxicity. Lethality studies determine the lethal dose for 50% of animals (LD50). Systemic toxicity parameters evaluated include effects on liver, kidney, heart and other organs. Toxicity studies provide safety information required for approval to conduct human clinical trials.
Assignment on Toxicokinetics- Toxicokinetic evaluation in preclinical studies, saturation kinetics Importance and applications of toxicokinetic studies. Alternative methods to animal toxicity testing.
This document discusses various types of animal toxicity studies conducted prior to clinical use of drugs in humans. It provides objectives and details of reproductive and developmental toxicity studies, local toxicity studies, carcinogenicity studies, and genotoxicity studies. Reproductive toxicity studies examine effects on fertility and development in offspring. Developmental toxicity studies evaluate effects during pregnancy and across lifespan. Local toxicity studies are required when drugs are administered via non-oral routes. Carcinogenicity studies identify substances that may induce or increase tumors.
In vivo is the Latin word which means with in the living body.
When effects of various biological entities are tested on whole, living organism or cells, usually animals including humans and plants.
Animal testing and clinical trials are major elements of in-vivo research.
In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject in drug discovery.
example, verification of efficacy in vivo is crucial, because in vitro assays can sometimes yield misleading results with drug.
Harry Smith found that sterile filtrates of serum from animals infected with Bacillus anthracis were lethal for other animals, whereas extracts of culture fluid from the same organism grown in vitro were not.
In microbiology Once cells are disrupted and individual parts are tested or analyzed, this is known as in vitro.
In vitro studies within the glass, i.e., in a laboratory environment using test tubes, petri dishes, etc. Examples of investigations in vivo include: the pathogenesis of disease.
In vitro toxicology:-
The bridge exists between new drug discovery and drug development.-
Provide information on mechanism of action of a drug
Provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate or to proceed further.
In vitro methods are widely used for:-
Screening and ranking chemicals
Get a platform for animal studies for physiological actions
Studying cell, tissue, or target specific effects
Improve subsequent study design
Advantages and Disadvantages:-
Faster than in vivo studies
Less expensive to run
Less predictive of toxicity in intact organisms
In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or observations made in vitro to predict phenomena in vivo, biological organisms.
The problem of transposing in vitro results is particularly acute in areas such as toxicology where animal experiments are being phased out and are increasingly being replaced by alternative tests.
Results obtained from in vitro experiments cannot often be directly applied to predict biological responses of organisms to chemical exposure in vivo.
Therefore, it is extremely important to build a consistent and reliable in vitro to in vivo extrapolation method.
Two solutions are now commonly accepted:
Increasing the complexity of in vitro systems where multiple cells can interact with each other in order recapitulate cell-cell interactions present in tissues (as in "human on chip" systems).
Using mathematical modeling to numerically simulate the behavior of a complex system, whereby in vitro data provides the parameter values for developing a model.
The two approaches can be applied simultaneously allowing in vitro systems to provide adequate data for the development of mathematical models. To comply with push for the development of alternative testing methods.
Experimental Techniques For Evaluation Of New Drugs.pptKarabiAdak
Experimental techniques are used to evaluate new drugs for toxicity, efficacy, and safety prior to human clinical trials. This includes acute and chronic toxicity studies in two animal species to identify target organ toxicity and establish a maximum tolerated dose. Genotoxicity and carcinogenicity studies are also conducted to assess genetic damage and cancer risk. Alternative methods seek to reduce animal testing through computer models, cell cultures, and organ-specific assays.
This document discusses various toxicokinetic studies conducted in preclinical stages of drug development. It describes conducting single dose, rising dose, repeated dose toxicity studies in rodents and non-rodents to determine kinetic parameters and assess safety. The importance of toxicokinetic data in setting safe clinical doses is highlighted. Alternative methods to animal testing like in vitro, in silico, cell line techniques and patch clamp method are also summarized.
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Denis is a dynamic and results-driven Chief Information Officer (CIO) with a distinguished career spanning information systems analysis and technical project management. With a proven track record of spearheading the design and delivery of cutting-edge Information Management solutions, he has consistently elevated business operations, streamlined reporting functions, and maximized process efficiency.
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Date: May 29, 2024
Tags: Information Security, ISO/IEC 27001, ISO/IEC 42001, Artificial Intelligence, GDPR
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Answers about how you can do more with Walmart!"
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Toxiocokinetic evaluation in preclinical studies.pptx
1. Kumaun University, bhimtal
Department of pharmaceutical sciences
Presented by Submitted to :
Manisha Jyala Dr. Tirath Kumar
M.Pharm 1st year(Pharmacology)
2. Toxicity + kinetics = kinetics of the toxic substance.
Kinetics stand for how a drug or toxic substance affected by a body in
terms of ADME.
Toxicokinetics is the science to understand what the body does with the
drug when the drug is given at relatively high doses.
Toxicokinetics play a major role in interpreting the histopathological
findings in a toxicological study.
It deals with the Absorption, distribution, biotransformation and excretion
of the chemicals.
3. To describe the systemic exposure achieved in animals and its
relationship to dose level and the time course of the toxicity study.
Assessing the clinical safety of a drug molecule by creating a relation
between the exposure achieved in toxicity studies and toxicological
findings.
Choosing the right animal species and proper treatment regimen during
preclinical studies.
To provide relevant data that helps in preparing the non clinical toxicity
study report.
4. 1. Quantification of exposure
2. Setting of dose level
• Low dose level
• Intermediate dose level
• High dose level
3. Complicating factors in exposure interpretation
4. Route of administration
5. Determination of metabolites
6. Statistical evaluation of data
7. reporting
5. The exposure might be represented by plasma concentrations or the AUG of
parental compound and sometimes by the tissue concentrations.
Quantification of exposure provides a assessment of burden on the test
species and helps in the interpretation of similarities and differences in
toxicity across species, dose groups .
When designing the toxicity studies, the exposure and dose dependence in
humans at therapeutic dose level should be considered in order to achieve the
relevant exposure at various dose level in animal toxicity studies.
6. Systemic exposure should be estimated in an appropriate number of
animals and dose group to provide a basis of risk assessment.
Both make and female animals are utilized in the main study it is normal
to estimate exposure in animals of both sexes unless some justification
can be made for not so doing.
7. Sample size is typically 0.25- 0.50 ml day in rodents and up to 1ml day in
non rodents.
The justification is made on kinetic data gathered from earlier toxicity
studies, from pilot or dose range finding studies, extrapolation.
Dose level for toxicity is largely regulated by toxicological findings and the
pharmacodynamic response of the test species.
Intermediate dose level should normally represent an appropriate multiple of
the exposure at lower dose level dependent upon the objective of the toxicity
study.
High dose level in toxicity studies will normally be determined by
toxicological considerations.
8. Pharmacokinetics is affected by the route.
For instance the orally administered drugs bioavailability time is more
than other routes.
If the drug is intended to administer through oral route then oral toxicity
is checked.
9. Large intra and inter individual variation of kinetic parameter may occur
and small number of animals are involved in generating toxic kinetic
data.
High level of precision in terms of statistics is not needed.
Consideration should be given to the calculation of mean or median
values and estimates the variability.
For evaluation validated analytical methods used and conforms to good
laboratory practices. Analytical method used in such studies include gas
chromatography, HPLC, LC and capillary electrophoresis.
10. 1. Safety assessment
2. Single dose and rising dose studies
3. Repeated dose toxicity studies
4. Genotoxicity studies
5. Reproduction toxicity studies
• Studies of fertility
• In pregnant and lactating animals
6. Carcinogenicity studies
11. Safety of a molecule can be performed in in vivo system .
This step is not included in guidelines but is useful for the researchers to
asses the systemic exposure of the molecule and its effect on it.
This safety study is integral part in the central nervous system ,
cardiovascular system and respiratory system.
12. These studies are often been performed in a very early phase of drug
development before a bioanalytical method has been developed.
These studies are usually performed on rodents.
Plasma samples may be taken in such studies and stored for later analysis.
13. For giving support for phase 1 studies this study is carried out for four
weeks in both rodents and non rodents.
Two in vitro studies and one in vivo study is essential to support
development of drug.
In vivo investigations usually use a rodents micronucleus (bone marrow
or peripheral erythrocytes ) test or chromosome aberration (bone marrow
cells) test.
These cells are well established studies for genotoxicity evaluation.
14. Reproduction toxicity measurements are taken in studies of fertility (rat),
embryo-foetal development (rat and rabbit) and peri- or post –natal
development.
(a) Studies of fertility
assessment of fertility toxicity has very important, because most of the drugs
used in fertility conditions so has to strengthen at that time.
(b) In pregnant and lactating animals
Data from non – pregnant animals is useful to set dose levels, and the
limitation of exposure is usually governed by maternal toxicity.
toxicokinetics may involve exposure assessment of embryos, foetuses or
new born at specific days.
15. Sometimes drugs are used for long time for curing purpose , this may
lead to toxicity or carcinogenicity.
So lifetime studies are needed in rodents to support the long term clinical
use of pharmaceuticals and non rodents are also used.
16. Also known as nonlinear pharmacokinetics.
The rate process of a drug ADME are dependent upon carrier or
enzymes that are substrate specific.
Have definite capacities and susceptible to saturationate high drug
concentration.
In such cases, an essentially first order kinetics transform into a mixture
of first order and zero order rate.
17. The transition from first order to saturation kinetics is important in
toxicology because it can lead to prolonged persistence of a compound in
the body after the acute exposure and excessive accumulation during
repeated exposures. In this condition the PK parameter change with the
size of administered dose
When plasma protein binding or elimination mechanism are saturated with
increasing dose , the pharmacokinetic parameter estimates the dose
dependent. When toxicant concentration exceed the capacity for
biotransformation by metabolic enzymes , overall clearance of the toxicant
decreases . they undergo non linear kinetics and this is known as saturation
toxicokinetics.
20. Toxicokinetics helps to deprive more precise information about kinetics and
metabolism of the drug study.
It also help to improve the assessment criteria of any new drug to attain
relevant data on safety and efficacy.
Use of few laboratory animals to provide data risk assessment purposes is
also important application of toxicokinetics.
Toxic kinetic studies proactively screen / evaluate leads at early stages
using predictive tools for toxicity and mechanism of action.
It help to develop preclinical biomarkers of drug response and toxicity.
21. It helps to increase the understanding of human variability of PK and PD
in target population.
Analysis of blood, tissue or excreta samples obtained during the conduct
of any other toxicity studies can provide data on bioavailability, changes
in plasma concentration in time , clearance rates, and bioaccumulation
potential.
Toxicokinetics study in pregnant animals can lead to determine the
extent of exposure of the foetus to study drug.