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Animal toxicology studies

Animal toxicology studies






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    Animal toxicology studies Animal toxicology studies Presentation Transcript

      • Benefit –risk ratio can be calculated
      • Prediction of therapeutic index
      • Therapeutic index= Maximum tolerated dose
      • Minimum curative dose
      • Smaller ratio, better safety of the drug
      • Pharmacological effects are same in man as in animals
      • Toxic effect in species will predict adverse effects in man
      • Giving high doses in animals improves predictability to man
      • Risk assessment can be made by comparison of toxic doses in test species with predicted therapeutic dose in man
    • 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
      • Studies should comply with GLP
      • Performed by trained and qualified staff
      • Use of standardized and calibrated equipment
      • SOP’s followed in laboratory tasks
      • All documents should be preserved for minimum 5 years after marketing of the drug
      • Generation of Pharmacokinetic data to access systemic exposure achieved in animals
      • Relation to dose level and the time course of toxicity study
      • To support choice of species & Treatment regimen
      • Design on clinical studies accordingly
      • Pharmacodynamic responses
      • Pharmacokinetic profile
      • Species, sex, age of experimental animals
      • Susceptibility, sensitivity and reproducibility of test system
      • In vitro: Isolated organs, tissues cell-cultures
      • Mechanism of effect in vivo
      • Systemic toxicology studies
      • Single dose studies Repeated dose studies
      • Reproductive toxicology studies
      • Male fertility Female reproduction & Developmental
      • studies
      • Local toxicity studies
      • Hypersensitivity studies
      • Genotoxicity studies
      • Carcinogenicity studies
      • Preliminary Definitive
      • Maximum Non Lethal dose
      • (MNLD) determined
      • MTD and MLD determined
      • Evaluate effects
      • Target organ of toxicity may be determined
      • METHOD
      • Single dose tested in 2 rodent species
      • 2 routes of administration
      • Oral dosing of 2g/kg or 10 times of normal human dose
      • Observation for 14 days after dosing
      • MNLD established
      • Symptoms , signs reported
      • Microscopic and Macroscopic evaluation
      • METHOD
      • Group of 20 animals of either sex dosed at MNLD
      • 5 animals of each sex are observed for 48 hr and conduct autopsy for early pathological changes
      • Remaining 5 of each sex are observed for 14 days
      • MTD and MLD established
      • Signs of intoxication or recovery, changes in body weight, pathological changes
      • Complete macroscopic and microscopic examination
      • Target organs can be identified
      • Two mammalian species(one should be non-rodent)
      • Long duration studies (30-180 days)
      • Dose is dependent on dose-escalating studies
      • Drug administered by clinical route
      • Parameters monitored and recorded are:
        • Behavioral
        • Physiological
        • Biochemical
        • Microscopic observations
      • METHOD
      • One rodent species(rat)
      • 3 dose groups taken
      • (each with 6 adult males),
      • 1 control
      • Drug treatment by clinical route for 28-72 days
      • Mated with females in 1:2 ratio
      • Females getting pregnant should be examined
      • After 13 days of gestation
      • All male animals sacrificed
      • Weights of testis, epididymus recorded & examined for their histology
      • Sperms examined for motility & morphology
      • Segment I
      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
      • Drug administered to both males (28days) and females (14 days) before mating
      Implantation Embryogenesis
      • Required when drug is administered by special route (other than oral) in humans
      • Study design:
        • 2 species along with control used
        • Dose dependent on dose escalating studies
        • 3 dose levels
      • Dermal toxicity studies
      • Dermal photo-toxicity studies
      • Vaginal toxicity studies
      • Rectal tolerance studies
      • Rats & Rabbit
      • Local signs (erythema, oedema), histological examination
      • Guinea pig
      • Used in treatment of leucoderma
      • Examination of erythema & oedema formation
      • Rabbit or Dog
      • Observation of swelling, histopathology of vaginal wall
      • Rabbit or Dog
      • Signs of pain, blood or mucous, histology examination of rectal mucosa
      • Ocular toxicity studies
      • Parenteral drugs
      • Inhalation toxicity studies
      • Albino Rabbit
      • Changes in cornea ,Iris & aqueous humor, histological examination of eye
      • For intravenous/ intramuscular/ subcutaneous/ intra-dermal injection
      • Sites of injection examined grossly and microscopically
      • One rodent and non rodent species
      • Acute , sub-acute and chronic studies performed
      • Observation of respiratory rate
      • Histological examination of respiratory passages, lung tissue
      • Guinea Pig Maximization test
      • Local lymph node assay
      • Determination of Maximum non irritant or minimum irritant dose
      • Evaluation of Erythema and oedema
      • Mice of one sex(either male or female)
      • Drug treatment given on ear skin
      • Auricular lymph node dissection after 5 days
      • Increase in 3h-thymidine used for evaluation
      • To detect early tumorigenic effects in cases of chronic illness
      • In vitro tests:
        • Test for gene mutation in Bacteria
        • Cytogenetic evaluation of chromosomal damage in mammalian cells
        • E.g .; Ames’s Salmonella Assay detects increased number of aberrations in metaphase chromosomes
        • DNA strand breaks, DNA repair or recombination, Measurements of DNA adducts
      • In vivo tests:
        • Chromosome damage in rodent hematopoietic cells
      • E.g .; Micronucleus Assay
      • Life-time Bioassays
      • Carcinogenicity studies are performed on:
      • Drug used for >6 months or frequent intermittent use for chronic diseases
      • Chemical structure of drug indicates carcinogenic potential
      • Therapeutic class of drugs which have produced positive carcinogenicity
      • Group sizes of 50 animals/sex at each of 3 dose levels
      • Control group is of double size
      • Record for onset of tumor development
      • Usually carried out for 24 months in rats and 18 months in mice (life span studies )
      • Incidence of cancers in control and test
      • Trend towards increasing incidence with increasing doses
      • Number of animals with single/multiple tumors
      • Macroscopic changes observed by autopsy
      • Histopathology of organs and tissues