Lecture 3 Preclinical

Question 1

preclinical testing

Answer 1

evaluate safety and efficacy of product before its use in humans

Question 2

definition toxicity

Answer 2

adverse effects of drug or chemial on body

Question 3

toxicokinectics

Answer 3

ADME of toxi chemical or dose

Question 4

genotoxicity

Answer 4

effet on cell DNA relates to cancer

Question 5

carcinogenicity

Answer 5

potential of chemical to cause cancer, tested in vivo only

Question 6

reproductive toxicity

Answer 6

effect of chemical on fertility and pregnany, in vivo only

Question 7

what to consider when choosing animal model

Answer 7

practicality (cost, transportation, care), scientific rationale (phylogenic and behavoural evolution, correlation with human trials), and animal welfare

Question 8

Canadian Council on Animal Care (CCAC) Three Rs

Answer 8

replacement, reuction, refinement (minimize pain and distress, increase welfare) - CCAC independent bdy sets guidelines and policies, responsible to public

Question 9

power analysis

Answer 9

the expected mean and variance of data to estimate the number of animals needed, based on previous studies

Question 10

pre-clinical safety development looking for… (4)

Answer 10

acute and chronic toxicity, genetic mutations, carcinogenicity, deformities in embroyos or foetuses

Question 11

ICH M3 (R2)

Answer 11

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

Question 12

genotoxicity and carinogenicity

Answer 12

identify tumorogenic potential in animals to assess risk in humans, for any drug whose expected clinical use is continuous fo 6 months or more

Question 13

considerations for carcinogenicity (5)

Answer 13

-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

Question 14

genotoxicity

Answer 14

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

Question 15

Toxicokinetics

Answer 15

-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

Question 16

acute toxicity studies

Answer 16

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

Question 17

repeated-dose toxicity studies

Answer 17

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

Question 18

Reproduction toxicity

Answer 18

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

Question 19

safety pharmacology studies

Answer 19

-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)

Question 20

Definition Product Monograph

Answer 20

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