Lecture 3 Preclinical Flashcards
preclinical testing
evaluate safety and efficacy of product before its use in humans
definition toxicity
adverse effects of drug or chemial on body
toxicokinectics
ADME of toxi chemical or dose
genotoxicity
effet on cell DNA relates to cancer
carcinogenicity
potential of chemical to cause cancer, tested in vivo only
reproductive toxicity
effect of chemical on fertility and pregnany, in vivo only
what to consider when choosing animal model
practicality (cost, transportation, care), scientific rationale (phylogenic and behavoural evolution, correlation with human trials), and animal welfare
Canadian Council on Animal Care (CCAC) Three Rs
replacement, reuction, refinement (minimize pain and distress, increase welfare) - CCAC independent bdy sets guidelines and policies, responsible to public
power analysis
the expected mean and variance of data to estimate the number of animals needed, based on previous studies
pre-clinical safety development looking for… (4)
acute and chronic toxicity, genetic mutations, carcinogenicity, deformities in embroyos or foetuses
ICH M3 (R2)
harmonize requirements for pre clinical safety studies in EU, Japan and US.
-charactertize toxic effects before given to humans
-estimation of initial safe starting dose and dose range for humans
genotoxicity and carinogenicity
identify tumorogenic potential in animals to assess risk in humans, for any drug whose expected clinical use is continuous fo 6 months or more
considerations for carcinogenicity (5)
-previous carcinogenic potential in product class for humans
-structure-activity relationship suggesting carcinogenic risk
-evidence of preneoplastic lesions with repeated dosing
-long-term tissue retention of compound or metabolites creating local tissue reactions or other pathphysiological responses
-typically need to be completed before market application, but not before clinical trials unless there is high risk
genotoxicity
in vitro studies and the test battery of in vitro and in vivo tests to reduce risk of false negative results for compounds with genotoxic potential
-detection of compounds that induce genetic damage by various mechanisms
-some compounds are mutagenic in vivo but not in vitro, therefore need both kinds of tests
Toxicokinetics
-assess systemic exposure
-what the body does with drug when given a relatively high dose relative to the therapeutic dose
-used in conjuction with data from toxiological studies for clinial safety
-helps decide animal models and tests for future preclinical studies
acute toxicity studies
toxcity prouced when drug administered in one or more doses in period not exceeding 24 hours
-uses route expected in clinical setting (ie oral) AND intravenous route
repeated-dose toxicity studies
duration of repeated dose animal toxicity studies in two or more mammalian species must be equal to or exceed the duration of the human clinical trials
-three different dose levels given daily over long period of time (low, intermediate, high)
-measure body weight, food/drink intake, blood, urine samples, and conc of test compound
Reproduction toxicity
reveal any effect of active substance on mammalian reprodution
-need at least one mammalian species
-look at fertility, embryonic and postnatal development
-must be done before giving drug to women of child-bearing age
typically use rats and rabbits
safety pharmacology studies
-identify potential undesirable pharmacodynamic effects of new drug
-evauate the adverse pharmacodynamic effects
-investigate mechanism of adverse effect
-cardiovascular, respiratory, CNS
-renal and GI system of less concern
-use ex vivo and in vitro tests (i. isolated tissues and organs, enzymes, etc)
Definition Product Monograph
factual scientific document on the drug product that does not contain promotional material
-includes properties, claims, indications, conditions of use, warnings, adverse reactions, drug interactions, dosage, and any other information relevant to safe and effective use
-physician information, scientific information, and consumer information
