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.
Use of mutants in understanding seedling development.pptx
toxicokinetics-1.pptx
1.
2. Toxicokinetics:
Toxicokinetics is the study of the drug movement around the body
(Absorption, Distribution, metabolism, and Elimination)
Toxicokinetic data is best derived using radio labeled dose of the
drug. This allows for following the fate of the drug, metabolic
products, distribution in the tissue, storage sites, as well as its
elimination. Unfortunately, these methods do not provide
knowledge about proportion of the drug left intact to its metabolites.
TK is concerned with what the body does to the toxicant.
3. TOXICODYNA
MICS:
Toxicodynamics is the study of toxic actions of xenobiotic
substances on living systems.
Toxicodynamics is concerned with processes and changes that
occur to the drug at the target tissue, including metabolism and
binding that results in an adverse effect.
Simply,TD is concerned with what the toxicant do to the body
4. RELATIONTO
PHARMACOKI
NETICS:
It is an application of pharmacokinetics to determine the
relationship between the systemic exposure of a compound in
experimental animals and its toxicity.
It is used primarily for establishing relationships between
exposures in toxicology experiments in animals and the
corresponding exposures in humans.
However, it can also be used in environmental risk assessments in
order to determine the potential effects of releasing chemicals
into the environment.
In order to quantify toxic effects toxicokinetics can be combined
with toxicodynamics. Such toxicokinetic-toxicodynamic (TKTD)
models
5. TOXICOKINETIC
PARAMETERS:
Absorption: Uptake of chemical into the lymph and blood
Distribution:Transport of chemical in blood and accumulation in
organs and tissues
Metabolism: Biotransformation into other products (metabolites)
Elimination: Excretion from the organism
6. HOW
TOXICOKINETICS
CAN INFLUENCE
THETOXICITY?
Absorption.
A toxic xenobiotic which is poorly absorbed may not cause
toxicity
Distribution
The distribution of a toxicant to a tissue other than the target
organ decreases its toxicity.
Metabolism (Biotransformation)
Two substances with equal absorption rate may differ in toxicity
depending on their biotransformation.
Elimination
The toxicity of xenobiotic depends on its elimination rate from
7. Examples of
how
toxicokinetics
of a substance
can influence
its toxicity:
Absorption — A highly toxic substance that is poorly absorbed
may be no more hazardous than a substance of low toxicity that is
highly absorbed.
Biotransformation —Two substances with equal toxicity and
absorption may differ in how hazardous they are depending on
the nature of their biotransformation.A substance that is
biotransformed into a more toxic metabolite (bioactivated) is a
greater hazard than a substancethat is biotransformed into a less
toxic metabolite (detoxified).
8. Routes of
Absorption
Inhalation – via the lungs
Direct contact – via the skin or eyes
Ingestion – via the gastrointestinal tract (GIT)
Injection – via direct puncture of the skin
In all routes of exposure, except injection, the chemical must cross a
biological membrane to enter the body – there are two main ways
this can occur:
Passive diffusion
Active transport
9. Absorption
Inhalation
Ingestion
Skin---Gases, vapours and particles - solid and liquid (aerosols).
Ingestion---Facial splashing, contaminated food, hand-to-mouth
behaviour.
Skin----Through or between cells, via sweat glands, sebaceous
glands or hair follicles.
10. Inhalation:
Usually main
route of
occupational
exposure
Lungs have
a large surface area,
Good blood supply,Thin membrane barrier,
High turnover of contents of lungs
Above factors lead to high potential for absorption of airborne
contaminants.
Once absorbed, distribution around body via bloodstream is rapid
In addition to absorption through lungs, insoluble particles such as
silica and asbestos can deposit in lungs and may lead to lung
damage
11. Passive
diffusion
Requires a positive concentration gradient i.e. substance tends to
diffuse across biological membrane from a high concentration to a
lower concentration.
Other factors that influence ability to cross biological membrane
include:
Lipid (or fat) solubility
Molecular size
Degree of ionisation
Generally, lipid soluble, small molecules that are non-ionised cross
biological membranes more easily.
12. Active
transport:
Involves a specific ‘carrier’ protein that transfers the xenobiotic
across the plasma membrane.
Can move molecules against a concentration gradient – requires
energy (ATP).
Mechanism particularly important in elimination of substances via
the kidney and liver by enabling active movement of water-
soluble substances across the largely fatty nature of the plasma
membrane.
13. Factors
determining
the severity of
toxicity
Duration and concentration
Rate and amount
Distribution
Efficiency
Ability
Amount and duration of storage
Age and health status.
14. Advantages of
toxicokinetics
Toxicokinetics is defined as the generation of pharmacokinetic 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.
These data may be used in the interpretation of toxicology findings
and their relevance to clinical safety issues.
Toxicokinetic measurements are normally integrated within the
toxicity studies and as such are described in this document as
'concomitant toxicokinetics'. Alternatively, data may be generated in
other supportive studies conducted by mimicking the conditions of
the toxicity studies.
Toxicokinetic procedures may provide a means of obtaining multiple
dose pharmacokinetic data in the test species, if appropriate
parameters are monitored, thus avoiding duplication of such studies;
optimum design in gathering the data will reduce the number of
animals required.
Various components of the total non-clinical pharmacokinetics and
metabolism programme may be of value in contributing to the
interpretation of toxicology findings. However, the toxicokinetic data
focus on the kinetics of a new therapeutic agent under the conditions
of the toxicity studies themselves.
15. Advantages of
toxicokinetics
It is an integral part of the non-clinical testing programme; it
should enhance the value of the toxicological data generated,
both in terms of understanding the toxicity tests and in
comparison with clinical data.
The need for toxicokinetic data and the extent of exposure
assessment in individual toxicity studies should be based on a
flexible step-by-step approach and a case-by-case decision
making process to provide sufficient information for a risk and
safety assessment.
16. The objectives
of
toxicokinetics
and the
parameters
which may be
determined
The primary objective of toxicokinetics 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.
17. Role of
toxicokinetics
in preclinical
drug
development
Toxicokinetics forms an essential part of the initial toxicity tests
done to screen for possible adverse effects; it is a vital component
of studies in healthy volunteers and patients, and it is usually
much involved in planning and interpreting specific experiments
done to explore the causes and nature of desired and adverse
effects.
18. The
toxicokinetic
questions
which should
be answered
early in
development
are:
Is the drug absorbed?
What is the relationship between the desired effect and the level
in a body fluid that can easily be monitored, such as blood urine?
What is the relationship between the applied dose and the effect
and the blood (or other medium) level?
How quickly and by what route or mechanisms is the drug cleared
from the body?
19. Clinical
development
and
toxicokinetics
and their
influenceon
preclinical
studies and their
interpretation
The basic need for toxicokinetics at the clinical level is much the
same as at the preclinical level, albeit with differences imposed by
the feasibility of acceptable investigations and the greater
heterogeneity of the populations studied.
The data gained can be used to refine subsequent toxicity tests
and mechanistic investigations, to explore the causes of target
organ and other forms of toxicity, to examine the sources of
unexpected therapeutic success or failure, and generally to refine
understanding of what the substance does and how it does it. •
Toxicokinetics is essential in planning rational and therefore
efficient toxicity tests, in analyzing drug effects in the target
species, and in adapting preclinical efficacy and toxicity
investigations to the specific properties of the development
compound.
20. General
principles to be
considered
Quantification of exposure
The quantification of systemic exposure provides an assessment
of the burden on the test species and assists in the interpretation
of similarities and differences in toxicity across species, dose
groups and sexes.The exposure might be represented by plasma
(serum or blood) concentrations or the AUCs of parent compound
and/or metabolite(s).
In some circumstances, studies may be designed to investigate
tissue concentrations.
21. Justification of time points for sampling
The time points for collecting body fluids in concomitant
toxicokinetic studies should be as frequent as is necessary, but not
so frequent as to interfere with the normal conduct of the study or
to cause undue physiological stress to the animals.
In each study, the number of time points should be justified on the
basis that they are adequate to estimate exposure.The
justification should be based on kinetic data gathered from earlier
toxicity studies, from pilot or dose range-finding studies, from
separate studies in the same animal model or in other models
22. Contribution
to the setting
of dose levels
in order to
produce
adequate
exposure
The setting of dose levels in toxicity studies is largely governed by
the toxicology findings and the pharmacodynamic responses of the
test species.
However, the following toxicokinetic principles may contribute to
the setting of the dose levels.
Low dose level
Intermediate dose level
High dose level
23. Extent of exposure assessment in toxicity studies
In toxicity studies, systemic exposure should be estimated in an
appropriate number of animals and dose groups to provide a basis
for risk assessment.
The number of animals to be used should be the minimum
consistent with generating adequate toxicokinetic data.Where
both male and female animals are utilised 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.
24. Complicating factors in exposure interpretation
Species differences in protein binding, tissue uptake, receptor
properties and metabolic profile should be considered. For
example, it may be more appropriate for highly protein bound
compounds to have exposure expressed as the free (unbound)
concentrations.
The pharmacological activity of metabolites, the toxicology of
metabolites and antigenicity of biotechnology products may be
complicating factors..
25. Route of administration
The toxicokinetic strategy to be adopted for the use of alternative
routes of administration, for example by inhalation, topical or
parenteral delivery, should be based on the pharmacokinetic
properties of the substance administered by the intended route.
26. Determination of metabolites
A primary objective of toxicokinetics is to describe the systemic
exposure to the administered compound achieved in the
toxicology species.
There may be circumstances when measurement of metabolite
concentrations in plasma or other body fluids is especially
important in the conduct of toxicokinetics.
27. Statistical evaluation of data
The data should allow a representative assessment of the
exposure.
However, because large intra- and inter-individual variation of
kinetic parameters may occur and small numbers of animals are
involved in generating toxicokinetic data, a high level of precision
in terms of statistics is not normally needed.
If data transformation (e.g. logarithmic) is performed, a rationale
should be provided.
28. Reporting
An outline of the analytical method should be reported or
referenced. In addition, a rationale for the choice of the matrix
analysed and the analyte measured should be given.
The positioning of the report within the application will depend
upon whether the data are specific to any one toxicity study or are
supportive of all toxicity testing.
29. Application of
toxicokinetics
in drug safety
and efficacy
more precise scenario of drug kinetics and metabolism;
improved assessment strategy with greater efficiency,
use fewer animals and provide better data for risk assessment purposes;
rescue at-risk programs in preclinical/early clinical development;
proactively screen/evaluate leads at early stages using predictive tools for
toxicity and mechanism of action;
develop pre-clinical biomarkers of drug response and toxicity;
adoption of toxicity management approaches to improve the therapeutic
outcomes.
An increased understanding of human variability of pharmacokinetics and
8pharmacodynamics in the population.
Further exploration of mode of action hypotheses (MoA).
Further application of biological modeling in the risk assessment of individual
chemicals and chemical mixtures.
Further identification and discussion of uncertainties in the modeling process.
Further use of "ReverseToxicokinetics," also called "IVIVE" (In vitro to in vivo
extrapolation).IVIVE in vitro data to estimate exposures that could be
associated with adverse effects in vivo.
Notas do Editor
To quantify the internal conc. Which is defined by uptake, eliminatio, and biotransformation and the processes that leads to the toxic effects.