Toxikokinetics

importance & applications.

1. ` KARNATAKA COLLEGE OF PHARMACY DEPARTMENT OF PHARMACOLOGY TOXICOLOGICAL SCREENING METHODS PRESENTATION ON IMPORTANCE AND APPLICATION OF TOXICOKINETIC STUDIES. SUBMITTED TO: DR.NAGARATHNA P.K.M. PREPARED BY: ARUN DEV POKHAREL II-SEM M.PHARM,PHARMACOLOGY

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. Toxicodynamics 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. Dosage Exposure Toxic Effects Plasma Conc. Site of action Toxicokinetics Toxicodynamics

5. Relation to Pharmacokinetics 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 are used in ecotoxicology.

6. Toxicokinetic (TK) processes xenobiotic ABSORPTION DISTRIBUTION METABOLISM EXCRETION EXTERNAL MEMBRANE BARRIERS skin G.I. tract lungs depots BLOOD PLASMA TISSUES PHASE-1 PHASE-2 KIDNEYS LIVER lungs saliva sweat breast milk

7. How toxicokinetics can influence the toxicity? 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 an organism.

8. Factors Determining the Severity of Toxicity Duration and concentration   Rate and amount   Distribution   Efficiency Ability   Amount and duration of storage   Age and health status.

9. 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).

10. Inter-Related Processes of Absorption, Distribution, Biotransformation, and Elimination

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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?

18. CLINICAL DEVELOPMENT AND TOXICOKINETICS AND THEIR INFLUENCE ON 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.

19. 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 allowing reliable extrapolation.

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. TOXICOKINETICS IN THE VARIOUS AREAS OF TOXICITY TESTING - SPECIFIC ASPECTS Single-dose toxicity studies These studies are often performed in a very early phase of development before a bioanalytical method has been developed and toxicokinetic monitoring of these studies is therefore not normally possible. Results from single-dose kinetic studies may help in the choice of formulation and in the prediction of rate and duration of exposure during a dosing interval. This may assist in the selection of appropriate dose levels for use in later studies.

30. Repeated-dose toxicity studies Toxicokinetics should be incorporated appropriately into the design of the studies. It may consist of exposure profiling or monitoring at appropriate dose levels at the start and towards the end of the treatment period of the first repeat dose study.

31. Genotoxicity studies For negative results of in vivo genotoxicity studies, it may be appropriate to have demonstrated systemic exposure in the species used or to have characterised exposure in the indicator tissue.

32. Carcinogenicity (oncogenicity) studies Sighting or dose-ranging studies The main studies

33. Reproductive toxicity studies Fertility studies Studies in pregnant and lactating animals

34.   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;

35. 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 pharmacodynamics in the population.

36. 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 "Reverse Toxicokinetics," 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 .

37. Use of Toxicokinetic Data from Toxicity Studies as Complementary Information. Analysis of blood, tissue and/or excreta samples obtained during the conduct of any other toxicity studies can provide data on bioavailability, changes in plasma concentration in time (AUC, Cmax ), bioaccumulation potential, clearance rates, and gender or life-stage changes in metabolism and kinetics.

38. Consideration of the study design can be used to answer questions relating to: saturation of absorption, biotransformation or excretion pathways at higher dose levels; the operation of new metabolic pathways at higher doses and the limitation of toxic metabolites to higher doses.

39. Other hazard assessment considerations could include issues such as: Age-related sensitivity due to differences in the status of the blood-brain barrier, the kidney and/or detoxification capacities; Sub-population sensitivity due to differences in biotransformation capacities or other TK differences; Extent of exposure of the foetus by transplacental transfer of chemicals or of the newborn through lactation.

40. THANK YOU