Lecture 8.3

Question 1

What may be the side effect of aspirin?

Answer 1

gastric irritation and bleeding

Question 2

What are the major objectives of preclinical safety studies?

Answer 2

◼ Provide assurance that it is safe to begin testing in humans.
◼ Support the selection of a dose to begin human trials.

Question 3

What are some key questions that have to be addressed in preclinical safety assessment?

Answer 3

1. enzymes involved in metabolism
2. How long and what route for elimination
3. repeated dosing affects which organ
4. any cardiovascular effect or cardiac conductance
5. effects on pulmonary function?
6. can be prepared according to GMP guidelines?

Question 4

What studies are used in pre clinical assessments to find out how long and by what routes the parent drug is eliminated?

Answer 4

Pharmacokinetics in rodent and non-rodent species; Radiolabelled drug-excretion-balance studies

Question 5

How is the impact of repeated dosing on organs assessed?

Answer 5

14-day to 3-month toxicology studies in a rodent and non-rodent species with toxicokinetics.

Question 6

How is it assessed whether the drug produces cardiovascular effects or cardiac conductance?

Answer 6

In vivo telemetry studies evaluating alterations in cardiac electrophysiology and cardiovascular vital signs; Action potential duration using isolated rabbit Purkinje fibers.

Question 7

How is it assessed whether the drug produces any effects on behavior or pulmonary function?

Answer 7

◼ Irwin behavior test in rats.
◼ Rat pulmonary function evaluation.

Question 8

What clinical responses are difficult to predict in animal studies?

Answer 8

nausea, dizziness, heartburn, or head-ache

Question 9

Preclinical development is an exercise that extrapolates nonhuman safety and efficacy information to a potential human outcome.

Answer 9

True

Question 10

What was the perceived advantage of thalodomide overs its counterparts?

Answer 10

as a soothing, sleep-inducing effects on patients without decreasing motor activity.

Question 11

Describe the ‘Jiggle Cage’ test in mice

Answer 11

-mice suspended over a sulfuric acid bath
-platinum wire hung from bottom of cage
-slightest movement of the mice caused the wire to dip into the sulfuric acid and produce H2

–> more hydrogen meant more active mice
–> used to test whether sedatives are effective

Question 12

What lead to Dr Frances O. Kelsey not approving thalidomide in the US?

Answer 12

The fact that no lethal dose for rats could be found suggested to her that the rats simply weren’t absorbing the
medicine.

Question 13

In what conditions does thalidomide prove to be effective?

Answer 13

• leprosy
• ENL
• myeloma

Question 14

Give 2 mechanism of actions of thalidomide

Answer 14

1. Inhibition of the growth and survival of stromal cells
2. Stimulation of T-cells

Question 15

What is the general difference between acute and subacute toxicity studies?

Answer 15

Acute: single dose treatment with increasing dose

Subacute: repeated-dose toxicity studies: dosing study in which animals are given repeated doses.

Question 16

What is the duration of acute and subacute toxicity studies?

Answer 16

acute: 14 day observation period

subacute: 2 weeks - 6 months

Question 17

What is the animal species which should be used for acute and subacute toxicity studies?

Answer 17

two different mammalian species

acute: 2 rodents –> mouse and rat

subacute: 1 rodent + 1 nonrodent

Question 18

What is the route of administration for preclinical toxicity studies?

Answer 18

both the intended clinical route and the intravenous route

Question 19

What is the acute single-dose study is now often designed to determine?

Answer 19

maximum tolerated dose (MTD)

as opposed to lethality dose

Question 20

What is meant by maximum tolerated dose (MTD) in toxicity?

Answer 20

highest daily dose of a chemical that does not cause overt toxicity in a 90-day
study in mice or rats.

Question 21

How is MTD determined in clinical trials?

Answer 21

by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.

Question 22

What is the data collected from acute and subacute studies used for?

Answer 22

1. establish a safe starting dose for humans
2. develop strategies for monitoring the subjects in clinical trails

Question 23

What is NOAEL (No observable adverse effect level)?

Answer 23

highest dose that does not produce any adverse (toxic) effect in the test animal species that is most relevant to humans or most sensitive to the toxic effects of the drug

–> estimation on highest starting dose in human

Question 24

What duration is considered sufficient for chronic toxicity study?

Answer 24

rodents: 6 month
non-rodents: 9 month

Question 25

In principle, the length of a chronic repeated dose study should be equal to, or longer than, the duration of the clinical trial up to the maximum recommended duration by regulatory authorities (i.e., 9 months) True or false

Answer 25

True

Question 26

Both subacute and chronic studies are repeated-dose toxicity studies. True or false

Answer 26

True

Question 27

the Guidance suggests that genotoxicity testing should be at least partially completed (specifically, in vitro assays for mutagenicity and chromosomal damage) by the time of first human exposure. However, the entire battery of testing, must be completed before Phase II trials.

Answer 27

True

Question 28

What is the purpose of reproductive toxicity?

Answer 28

to assess the drug’s potential effect on mammalian reproduction.

Question 29

How are reproductive toxicity study generally carried out?

Answer 29

in rats (sometimes rabbits), by dosing animals prior to and during pregnancy and then following the effects through the next generation’s reproductive cycle.

Question 30

What is the three-study combination recommended by ICH for reproductive toxicity?

Answer 30

1. Fertility and early embryonic development 2. Pre- and post-natal development 3. Embryo-fetal development --> effects on hormonal cycles, pregnancy and embryo development are monitored.

Question 31

When are caricnogenicity studies required?

Answer 31

in cases where the drug is to be administered over a long period (e.g., 3 months) to human subjects

Question 32

In what circumstances are carcinogenicity studies exempted?

Answer 32

drugs that are not systemically bioavailable (i.e., topical drug administration); or endogenous peptides or proteins

Question 33

How are carcinogenicity studies carried out?

Answer 33

long term study (2-3 yrs) in rodents to test for tumor. organs/tissues from animals tested daily

Question 34

What are some examples of carcinogenicity models?

Answer 34

transgenic mouse models such as p53(+/-), Tg.AC, and TgHras models

Question 35

What kind of data is collected during carcinogenicity studies?

Answer 35

hormone levels, growth factors, and tissue enzymatic activities

Question 36

Is carcinogenicity study required prior to initiation of clinical trials?

Answer 36

No. Rather, they are usually completed in time to support the application for marketing approval

Question 37

What is the purpose of mutagenicity studies?

Answer 37

The potential for a drug to cause genetic damage to cells will be assessed.

Question 38

How are mutagenicity studies carried out?

Answer 38

In vitro tests: mammalian cells are used to see if the drug causes genetic changes or damage to chromosomes mice: treated with the drug will be examined for specific changes in cells from blood and bone marrow