3 repeated dose and other toxicity tests Flashcards
what is the point of sub-chronic toxicity studies?
-to assess potential toxicity resulting from repeated (daily) exposure over a 28 or 90 day period
-to stimulate a more common form of human exposure to drugs that don’t exert immediate toxic effects (e.g. paroxetine=antidepressant that accumulates in fat and only see effects when lose weight)
-identify the maximum tolerated dose (MTD)
-insight into appropriate doses for chronic and carcinogenicity studies
what is the animal model in sub-chronic toxicity studies?
-preferred species is the rat (mice have very little amount of blood)
-at least 20 animals (10 female and 10 male) for each dose level
-number of animals can be increased based on interim kills planned and satellite groups (not part of 20 animals)
-weight variation of the animal should be minimal (not exceed +-20% of the mean weight of each)
-dosing should begin as soon as possible after weaning (<9 weeks old)
what are the housing and feeding conditions of sub-chronic toxicity studies?
-same as for acute toxicity studies
-animals are housed individually, or caged in small groups of the same sex
what is the dosage for sub-chronic toxicity studies?
-at least three dose levels (daily) and a control (untreated or a vehicle-control group which is the formulation with no drug)
-highest dose should induce toxicity but not death or severe suffering
-descending sequence of dose levels ( two- to four- fold intervals are optimal) (larger dosing differences)
-dosed daily seven days each week for a period of 28 or 90 days (depending on the objective of the study)
-preparation and administration of doses same as for acute toxicity tests (don’t change anything)
what are the observation being made in sub-chronic toxicity studies?
-general clinical observation should be made once a day
-changes in the skin, fur, eyes, mucous membranes, occurrence of secretions
-changes in gait, posture and response to handling (anything affecting CNS)
-body weight, food consumption: at least once a week
-hematology and clinical biochemistry
-pathology
what are the observations made at the end of test period in sub-chronic toxicity studies?
-hematology: hemoglobin concentration, erythrocyte, leucocyte, platelet count, etc
-clinical biochemistry: to investigate major toxic effects on kidney and liver (markers and enzymes we could look at)
-pathology: all animals should be subjected to a detailed gross necroscopy, including full histopathology as well
what are chronic toxicity studies?
-daily administration in graduated doses to different groups in 12 months (still using rodents)
-oral route (preferable) although inhalation or dermal route may also be appropriate (depending on use)
-the identification of the chronic toxicity of a substance, and prediction of chronic toxicity effects at human exposure levels
-should only be carried out after initial information on toxicity collected from 28-day and/or 90-day toxicity tests
what is the animal models for chronic toxicity studies?
-for rodents, at least 20 animals per sex group (at each dose level)
-for non-rodents (rabbits, dogs), a minimum of 4 per sex group
-may also include one or more interim kills (e.g. at 3 and 6 months: to get idea of pathology, if something is going on with organs)
what is the dosage of chronic toxicity studies?
-at least three dose levels and a control (untreated or a vehicle-control group)
-based on the previous studies (sub-chronic)
-descending sequence f dose levels (two- to four-fold intervals are optimal)
-dosed daily seven days each week for a period of 1 year
-preparation and administration of doses same as for acute toxicity tests
what are the observations made in chronic toxicity studies?
-all animals should be checked twice a day for morbidity or mortality
-general clinical observations at least once a day
-detailed clinical observation: at the end of the first week of the study, and monthly thereafter
-body weight/food consumption: at least once a week for the first 13 weeks, and at least monthly thereafter
-hematological examinations (rodent): at least 10 each sex per group at 3, 6 and 12 months
-pathology: all animals should be subjected to a detailed gross necroscopy, including full histopathology as well
what are carcinogenicity studies?
-to determine the oncogenic potential of the drug in animals to assess the relevant risk in humans
-for some drugs, there is a concern for their potential mitogenicity or demonstrated immunosuppression
-does the pharmacology indicate some risk and the need for an assessment (if know the mechanism, you could predict carcinogenesis pathways that may be induced)
-when carcinogenicity studies are required they usually need to be completed before application for marketing approval (can do while or before clinical trials)
when are carcinogenicity studies not needed?
-pharmaceuticals with clinical dosing <6 months (if treatment is less than 6 months, such as antibiotics)
-life expectancy of the indication is <2-3 years (if diagnosed will only survive for few years, so they prolong life but do not cure)
-replacement therapy (endogenous substance) (such as insulin)
when are carcinogenicity studies needed (causes for concern: red flags)?
trumps what not needed for (must test if fail one)
-carcinogenic potential in the product class (already know potential of cancer based on class or functional group)
-structure-activity relationship (SAR) suggesting carcinogenic risk (functional groups)
-preneoplastic lesions (precursor to a tumor) in the repeated dose studies (based on pathology report)
-long-term tissue retention of parent compound (active ingredient that was defined first) or metabolite(s)-> local tissue reactions (concentration of drug will increase overtime in cells, therefore odds of the lesions will go up)
what are the animal models and dose selection of carcinogenicity studies?
animal models: rats and mice
-at least 50 animals of each sex (per group)
dose selection: based on previous repeated-dose toxicity studies (need idea for what dose is safe)
what is the duration and endpoints of carcinogenicity studies?
duration: 24 months
endpoints
-clinical observations
-hematology
-pathology
what is reproductive toxicity?
adverse effects
-males: sexual behavior/libido, fertility, and pregnancy outcomes
-female: sexual behavior/libido, onset of puberty, fertility, gestation, parturition, lactation or premature reproductive senescence
what is developmental toxicity?
occurrence of adverse effects on the developing organism
-manifested as death, structural abnormality or functional deficiency
when are reproductive and developmental toxicity studies needed?
it is required for any drugs to be used in women of childbearing potential, regardless of whether the target population is pregnant women (why might sign contract saying won’t get pregnant during treatment)
who do we test reproductive and developmental toxicity studies on?
-women of non-childbearing potential (i.e. permanently sterilized, postmenopausal), and men can be included in Phase I and II clinical trials if relevant repeated-dose toxicity studies have been conducted (evaluation of the reproductive organs)
-fertility study is required prior to phase III trials (reproductive toxicity studies)
-pre- and postnatal development study is required for marketing approval
what are the three-segment testing protocol of reproductive and developmental toxicity studies?
-fertility and general reproductive performance (segment I) involves study of both male and female rat
-teratology o embryo-fetal toxicity studies (segment II) conducted in rat and rabbit
-perinatal and postnatal development (segment III) conducted in the rat to evaluate drug effects during the last trimester of pregnancy and the period of lactation
what are reproductive and developmental toxicity studies based on?
-high dose should be selected to produce minimal toxicity (based on data from previous studies)
-ICH guidelines recommends at least three dose groups and control (dont suggest # of animals or order of dosing)
what are some other toxicity studies?
not very humane
-ocular toxicity testing (ocular lesions)
-dermal toxicity testing (dermal reactions)
