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Kumaun University, bhimtal
Department of pharmaceutical sciences
Presented by Submitted to :
Manisha Jyala Dr. Tirath Kumar
M.Pharm 1st year(Pharmacology)
 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.
 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.
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
 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.
 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.
 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.
 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.
 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.
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
 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.
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.
 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.
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.
 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.
 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.
 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.
Toxiocokinetic evaluation in preclinical studies.pptx
1. Drug absorption
2. Drug distribution
3. Drug metabolism
4. Drug excretion
 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.
 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.

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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.
  • 19. 1. Drug absorption 2. Drug distribution 3. Drug metabolism 4. Drug excretion
  • 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.