Animal toxicology studies


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Animal toxicology studies

  2. 2. <ul><li>Benefit –risk ratio can be calculated </li></ul><ul><li>Prediction of therapeutic index </li></ul><ul><li>Therapeutic index= Maximum tolerated dose </li></ul><ul><li> Minimum curative dose </li></ul><ul><li>Smaller ratio, better safety of the drug </li></ul>
  3. 3. <ul><li>Pharmacological effects are same in man as in animals </li></ul><ul><li>Toxic effect in species will predict adverse effects in man </li></ul><ul><li>Giving high doses in animals improves predictability to man </li></ul><ul><li>Risk assessment can be made by comparison of toxic doses in test species with predicted therapeutic dose in man </li></ul>
  4. 4. PHASES OF DRUG DEVELOPMENT (ANIMAL MAN) PHASE III PHASE IV PHASE I PHASE I PRECLINICAL PHASE II Product Approval (NDA/MAA) Patient studies Entry to man (IND / CTA) None Healthy subjects Safety and tolerability Genetic toxicity (in vivo) Repeat dose toxicity testing + Bioanalysis / Toxicokinetics Drug Metabolism Reproductive Toxicity Testing (teratogenicity) Patients Small scale efficacy studies Patients Large scale multicentre studies Chronic (long term) toxicity testing + Bioanalysis / Toxicokinetics Reproductive Toxicity Testing (fertility and pre/post natal) Carcinogenicity studies Drug Metabolism Patients Large scale post-marketing studies As required Genetic toxicity (in vitro) Single / repeat dose toxicity studies + Bioanalysis / Toxicokinetics Safety Pharmacology Drug Metabolism Lead candidate Identified Clinical Non-clinical MOLECULE
  5. 5. <ul><li>Studies should comply with GLP </li></ul><ul><li>Performed by trained and qualified staff </li></ul><ul><li>Use of standardized and calibrated equipment </li></ul><ul><li>SOP’s followed in laboratory tasks </li></ul><ul><li>All documents should be preserved for minimum 5 years after marketing of the drug </li></ul>
  6. 6. TOXICOKINETIC STUDIES <ul><li>Generation of Pharmacokinetic data to access systemic exposure achieved in animals </li></ul><ul><li>Relation to dose level and the time course of toxicity study </li></ul><ul><li>To support choice of species & Treatment regimen </li></ul><ul><li>Design on clinical studies accordingly </li></ul>
  7. 7. <ul><li>Pharmacodynamic responses </li></ul><ul><li>Pharmacokinetic profile </li></ul><ul><li>Species, sex, age of experimental animals </li></ul><ul><li>Susceptibility, sensitivity and reproducibility of test system </li></ul><ul><li>In vitro: Isolated organs, tissues cell-cultures </li></ul><ul><li>Mechanism of effect in vivo </li></ul>
  8. 8. <ul><li>Systemic toxicology studies </li></ul><ul><li>Single dose studies Repeated dose studies </li></ul><ul><li>Reproductive toxicology studies </li></ul><ul><li>Male fertility Female reproduction & Developmental </li></ul><ul><li>studies </li></ul><ul><li>Local toxicity studies </li></ul><ul><li>Hypersensitivity studies </li></ul><ul><li>Genotoxicity studies </li></ul><ul><li>Carcinogenicity studies </li></ul>
  9. 9. <ul><li>Preliminary Definitive </li></ul><ul><li>Maximum Non Lethal dose </li></ul><ul><li>(MNLD) determined </li></ul><ul><li>MTD and MLD determined </li></ul><ul><li>Evaluate effects </li></ul><ul><li>Target organ of toxicity may be determined </li></ul><ul><li>SINGLE DOSE STUDIES/ ACUTE TOXICITY </li></ul>
  10. 10. <ul><li>METHOD </li></ul><ul><li>Single dose tested in 2 rodent species </li></ul><ul><li>2 routes of administration </li></ul><ul><li>Oral dosing of 2g/kg or 10 times of normal human dose </li></ul><ul><li>Observation for 14 days after dosing </li></ul><ul><li>MNLD established </li></ul><ul><li>Symptoms , signs reported </li></ul><ul><li>Microscopic and Macroscopic evaluation </li></ul>
  11. 11. <ul><li>METHOD </li></ul><ul><li>Group of 20 animals of either sex dosed at MNLD </li></ul><ul><li>5 animals of each sex are observed for 48 hr and conduct autopsy for early pathological changes </li></ul><ul><li>Remaining 5 of each sex are observed for 14 days </li></ul><ul><li>MTD and MLD established </li></ul><ul><li>Signs of intoxication or recovery, changes in body weight, pathological changes </li></ul><ul><li>Complete macroscopic and microscopic examination </li></ul><ul><li>Target organs can be identified </li></ul>
  12. 12. <ul><li>Two mammalian species(one should be non-rodent) </li></ul><ul><li>Long duration studies (30-180 days) </li></ul><ul><li>Dose is dependent on dose-escalating studies </li></ul><ul><li>Drug administered by clinical route </li></ul><ul><li>Parameters monitored and recorded are: </li></ul><ul><ul><li>Behavioral </li></ul></ul><ul><ul><li>Physiological </li></ul></ul><ul><ul><li>Biochemical </li></ul></ul><ul><ul><li>Microscopic observations </li></ul></ul>b) REPEATED DOSE STUDIES/SUB-ACUTE OR CHRONIC TOXICITY
  13. 13. <ul><li>a) MALE FERTILITY </li></ul><ul><li>METHOD </li></ul><ul><li>One rodent species(rat) </li></ul><ul><li>3 dose groups taken </li></ul><ul><li>(each with 6 adult males), </li></ul><ul><li>1 control </li></ul><ul><li>Drug treatment by clinical route for 28-72 days </li></ul>
  14. 14. <ul><li>Mated with females in 1:2 ratio </li></ul><ul><li>Females getting pregnant should be examined </li></ul><ul><li>After 13 days of gestation </li></ul><ul><li>All male animals sacrificed </li></ul><ul><li>Weights of testis, epididymus recorded & examined for their histology </li></ul><ul><li>Sperms examined for motility & morphology </li></ul>
  15. 15. <ul><li>Segment I </li></ul>Fertility and general reproductive performance study Segment II Teratogenicity Segment III Peri and post-natal study Fertility and early embryonic development (rat) Embryo- foetal development (rat & rabbit) Post natal development (rat) (post natal survival of offspring), growth parameters, vital senses, behavioral effects <ul><li>b) FEMALE FETILITY </li></ul><ul><li>Drug administered to both males (28days) and females (14 days) before mating </li></ul>Implantation Embryogenesis
  16. 16. <ul><li>Required when drug is administered by special route (other than oral) in humans </li></ul><ul><li>Study design: </li></ul><ul><ul><li>2 species along with control used </li></ul></ul><ul><ul><li>Dose dependent on dose escalating studies </li></ul></ul><ul><ul><li>3 dose levels </li></ul></ul>
  17. 17. <ul><li>Dermal toxicity studies </li></ul><ul><li>Dermal photo-toxicity studies </li></ul><ul><li>Vaginal toxicity studies </li></ul><ul><li>Rectal tolerance studies </li></ul><ul><li>Rats & Rabbit </li></ul><ul><li>Local signs (erythema, oedema), histological examination </li></ul><ul><li>Guinea pig </li></ul><ul><li>Used in treatment of leucoderma </li></ul><ul><li>Examination of erythema & oedema formation </li></ul><ul><li>Rabbit or Dog </li></ul><ul><li>Observation of swelling, histopathology of vaginal wall </li></ul><ul><li>Rabbit or Dog </li></ul><ul><li>Signs of pain, blood or mucous, histology examination of rectal mucosa </li></ul>
  18. 18. <ul><li>Ocular toxicity studies </li></ul><ul><li>Parenteral drugs </li></ul><ul><li>Inhalation toxicity studies </li></ul><ul><li>Albino Rabbit </li></ul><ul><li>Changes in cornea ,Iris & aqueous humor, histological examination of eye </li></ul><ul><li>For intravenous/ intramuscular/ subcutaneous/ intra-dermal injection </li></ul><ul><li>Sites of injection examined grossly and microscopically </li></ul><ul><li>One rodent and non rodent species </li></ul><ul><li>Acute , sub-acute and chronic studies performed </li></ul><ul><li>Observation of respiratory rate </li></ul><ul><li>Histological examination of respiratory passages, lung tissue </li></ul>
  19. 19. <ul><li>Guinea Pig Maximization test </li></ul><ul><li>Local lymph node assay </li></ul><ul><li>Determination of Maximum non irritant or minimum irritant dose </li></ul><ul><li>Evaluation of Erythema and oedema </li></ul><ul><li>Mice of one sex(either male or female) </li></ul><ul><li>Drug treatment given on ear skin </li></ul><ul><li>Auricular lymph node dissection after 5 days </li></ul><ul><li>Increase in 3h-thymidine used for evaluation </li></ul>
  20. 20. <ul><li>To detect early tumorigenic effects in cases of chronic illness </li></ul><ul><li>In vitro tests: </li></ul><ul><ul><li>Test for gene mutation in Bacteria </li></ul></ul><ul><ul><li>Cytogenetic evaluation of chromosomal damage in mammalian cells </li></ul></ul><ul><ul><li>E.g .; Ames’s Salmonella Assay detects increased number of aberrations in metaphase chromosomes </li></ul></ul><ul><ul><li>DNA strand breaks, DNA repair or recombination, Measurements of DNA adducts </li></ul></ul><ul><li>In vivo tests: </li></ul><ul><ul><li>Chromosome damage in rodent hematopoietic cells </li></ul></ul><ul><li>E.g .; Micronucleus Assay </li></ul>
  21. 21. <ul><li>Life-time Bioassays </li></ul><ul><li>Carcinogenicity studies are performed on: </li></ul><ul><li>Drug used for >6 months or frequent intermittent use for chronic diseases </li></ul><ul><li>Chemical structure of drug indicates carcinogenic potential </li></ul><ul><li>Therapeutic class of drugs which have produced positive carcinogenicity </li></ul>
  22. 22. <ul><li>Group sizes of 50 animals/sex at each of 3 dose levels </li></ul><ul><li>Control group is of double size </li></ul><ul><li>Record for onset of tumor development </li></ul><ul><li>Usually carried out for 24 months in rats and 18 months in mice (life span studies ) </li></ul>CONDUCT OF STUDY
  23. 23. EVALUATION OF RESULT <ul><li>Incidence of cancers in control and test </li></ul><ul><li>Trend towards increasing incidence with increasing doses </li></ul><ul><li>Number of animals with single/multiple tumors </li></ul><ul><li>Macroscopic changes observed by autopsy </li></ul><ul><li>Histopathology of organs and tissues </li></ul>