Toxiocokinetic evaluation in preclinical studies.pptx

its importance in education

1. Toxiocokinetic evaluation in preclinical studies Kumaun U niversity, bhimtal Department of pharmaceutical sciences Presented by Submitted to : Manisha Jyala Dr. Tirath K umar M.Pharm 1 st year(Pharmacology)

2. TOXICOKINETICS 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. Aim of toxicokinetic studies 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. General principles to be considered Quantification of exposure 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. Quantification and extent of exposure 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. Extent of exposure 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. Sampling points and dose level setting 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. Route of administration 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. Statistical evaluation of data and analytical methods 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. Toxicokinetic studies in preclinical stage Safety assessment Single dose and rising dose studies Repeated dose toxicity studies Genotoxicity studies Reproduction toxicity studies Studies of fertility In pregnant and lactating animals 6. Carcinogenicity studies

11. Safety Assessment 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. SINgle dose and rising dose studies 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. Repeated dose toxicity and genotoxicity studies 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 studies 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. Carcinogenicity studies 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. Saturation kinetics 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.

18. Causes of non linearity Drug absorption Drug distribution Drug metabolism Drug excretion

19. Applications Of Toxicokinetics 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.

20. 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 .