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.

1. IMPORTANCE AND
APPLICATIONS OF
TOXICOKINETIC STUDIES
NOIDA INSTITUTE OF ENGINEERING AND
TECHNOLOGY
(PHARMACY INSTITUTE) GREATER NOIDA
Presented by :-
Vishnu Prabhakar
M.Pharm(Pharmacology)
Submitted to :-
Dr. Saumya Das
Associate Professor
NIET (Pharmacy Institute)
Greater Noida
Credits:- goodhousekeeping.com

2.  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."

3. 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.

4.  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.

5.  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.

6.  Toxicokinetics is largely reflective of the ADME of a molecule as it moves through
the body of an organism. As with all animal studies, interspecies differences in
ADME should be considered prior to clinical human testing and during data
extrapolation.
 If correctly utilized, Toxicokinetics studies can provide quantifiable endpoints to
better explain negative effects that may arise during toxicity studies.
 Toxicokinetics studies is to describe the systemic exposure achieved in animals
and its relationship to dose level and the time course of the toxicity study.
Increased implementation of toxicokinetic sampling in all stages of toxicity testing
could provide significant improvement in terms of efficiency, relevance, reliability,
time constrains and budget.

7.  Generation of kinetic data for systemic exposure and toxicity assessment of the drug.
 Simply it means if the safety/risk ratio is balanced, or safety is more then it will be
used as good therapeutic agent.
 Important in drug development stages especially in preclinical stage.
 TK evaluation is useful for the setting safe dose level in clinical phases.
 TK evaluation is useful in selection of dose, dosing form, alternative dosing route,
evaluation of toxicological mechanism, and also used for the setting safe dose level in
clinical phases.
 TK studies also used to reduce the animal number.

8.  TK evaluation is very important in drug development phase in both regulatory and scientific
perspective.
 TK data are practically used for the purpose of drug discovery such as lead-optimization and
candidate-selection.
 Toxicokinetic data is important to know the toxic response to that of drug exposure obtained in
drug development stages.
 It is used to set safe dose for clinical use of new drugs.
 Useful in the understanding of differences in responses or sensitivity between individual
animals, genders, species or life stages, and supporting the extrapolation of findings in
experimental animals to humans.
 Even though toxicokinetic evaluation is only a small part of the process of understanding the
fate of a drug, it has a vital part in drug development a role that proceeds to advance.

9.  Studies reveal the drug toxicity at molecular as well as genetic level that helps
researchers and physicians to reduce the undesired effects of drug.TK/TD/TG
approaches are very important to develop experiments designed to understand the
molecular basis of drug toxicities.
 Toxicokinetics evaluation is important in drug development stages. This
evaluation should constitute effective analytical methods having good accuracy
and precision, adequate sampling, drug and metabolites evaluation both in
animals and humans and sufficient results evaluation.
 Toxicokinetics data is important to know the toxic responses to that of drug in
preclinical which can be used to set safe dose for clinical use of new drugs. It also
gives support to mode of action analysis and extrapolation across exposure routes.

10.  Toxicokinetics used in other areas of pharmacokinetics which act as a biomarkers
for doing screening studies which provide data for allometric species scaling,
measuring drug levels in non-plasma samples (tissues, urine and bile). Even
though toxicokinetics evaluation is only a small part of the process of
understanding the fate of a drug, it has a vital part in drug development.
 The evolution of toxicity whether as discrete or sequential, single or multiple
events, each effects measured or observed can be identified by toxicokinetic data.
 The route of administration and the nature of the formulation to be used in
humans, as well as the therapeutic indication for which the compound is intended
can also be detected.

11. REFERENC
E
 Chasseaud LF. The importance of
pharmacokinetic/toxicokinetic and
metabolic information in carcinogenicity
study design. Drug Information Journal.
1992 Jul;26(3):445-55.