Exam 2 lecture 12

Question 1

preclinical testing, research & development time range

Answer 1

1-3 years

avg: 18 mo

Question 2

clinical research & development time range

Answer 2

2-10 years

avg: 5 yrs

Question 3

NDA review time range

Answer 3

2mo-7yrs

avg:24 mo

Question 4

phase 1

Answer 4

PK
dose-escalation study
safety (side effects)
in vivo biomarkers (initial response)

Question 5

phase 2

Answer 5

initial antitumor efficacy
safety (Side effects)
in vivo biomarkers
PK

Question 6

phase 3

Answer 6

clinical efficacy

safety & population PK

Question 7

is phase 4 required?

Answer 7

no

Question 8

purpose of preclinical studies

Answer 8

• establish a safety profile in ANIMALS prior to human use
• predict potential toxicity in humans
• provide rationale for studies in humans

Question 9

implication of preclinical data

Answer 9

• provide basic pharmacology & toxicology info
• determine if the drug is sufficiently safe for human use
• provide data for continued use once clinical trials begin
• provide data for use in larger pt population or longer period
• predict potential toxicity in humans
• provide rationale for studies in humans
• determine side effects that are impractical or unethical to investigate in humans

Question 10

animal commonly used to study HIV

Answer 10

monkey

Question 11

animal commonly used to study CV

Answer 11

rabbits and dogs

Question 12

animal commonly used to study toxicology & cancer

Answer 12

rates & mice

Question 13

preclinical studies pharmacology profile

Answer 13

• MOA
• dose response relationship
• duration of action
• effects on major systems
• ADME

Question 14

preclinical studies pharmacology screening

Answer 14

• to determine any pharmacologic action

- - CNS, CV system, autonomic nervous system, respiratory system, GI system, GU system

Question 15

in vitro pharmacology study

Answer 15

• biochemical/pharmaceutical properties
• in vitro stability
• solbulity
• stability in cell culture/tissue culture
• plasma protein binding
• in vitro metabolism, cellular uptake, PK and PD

Question 16

in vivo pharmacology study

Answer 16

• pharmacological effetcs
• effects on target site/system
• effects on other systems (animal model, readouts)
• data analysis
• implication in clinical trials

Question 17

preclinical studies: toxicology

Answer 17

• aid in deciding if a drug should be tested in humans
• forewarn or predict potential hazards in humans
• define potential toxic or harmful effects of drugs in animals

Question 18

types of toxicology testing

Answer 18

acute
subchronic
carcinogenicity
reproduction & teratology
mutagenicity

Question 19

subchronic toxicology data implication

Answer 19

MOA
pharmacologic activity
target organs
dose-response relationship
sex difference

Question 20

chronic toxicity testing protocol

Answer 20

duration: 3-12 months
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use

Question 21

carcinogenicity testing protocol

Answer 21

duration: 2 years
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use
observation: cancerous growth

Question 22

reproductive & teratology testing

Answer 22

1. fertility & general reproductive performance
2. teratology
3. prenatal & postnatal study

Question 23

toxicogenomic approaches

Answer 23

• link biological response to differential gene expression
• animal study (3 groups- vehicle control, low dose & high dose treatment)
• RNA microarray

Question 24

disease research purposes:

Answer 24

1. recognize subdivision of disease, leading to better testing model for testing of new therapy
2. ID biomarker for preclinical & clinical trials
3. ID disease mechanisms, leading to drug target ID & validation
4. ID common links between diseases previously thought to be unrelated

Question 25

acute modulation of target expresssion

Answer 25

transcription | translation

Question 26

chronic modulation of target expression

Answer 26

- transgenic approach aka knock-in(overexpression of target gene) - knock-out mice - knock-down approaches

Question 27

what is the role of a protein in biological effects?

Answer 27

increase activity>> overexpression | decrease activity>> inhibition (better model for drug action)

Question 28

RNA interference (RNAi)

Answer 28

- easy to ID potent siRNA - highly selective for target mRNA - only sequence info required - can be used both in vivo & in vitro - potential for high throughput screening - high efficacy - difficult to deliver - uncertain effects in vivo - stabilizing in vivo - selectivity in vivo to be determined

Question 29

antibodies

Answer 29

- knowledge of target is required - multiple targets frequent - PK issues: ADME - difficult to deliver - slow & time consuming - therapeutic potential

Question 30

modulation of protein function

Answer 30

- antibodies - dominant negative proteins - aptamers

Question 31

animal models that should represent chronic diseases

Answer 31

are difficult to model | e.g. COPD due to continuous exposure to smoke

Question 32

animal models that should represent phenotypes

Answer 32

are difficult to define & measure | e.g. psychiatry (schizo, depression)

Question 33

model organisms all to ID novel targets and pathways

Answer 33

drosophila C. Elegans zebrafish

Question 34

mouse models

Answer 34

- transgenic - knock-in/knock-out - knock-down

Question 35

zebrafish

Answer 35

- vertebrate whole animal in vivo model - rapid embryogenesis & organogenesis - easy development of visual & function screens - large numbers of animals available for HTS - cost-effective screening - large sample size for statistical analysis

Question 36

angiogenesis & zebrafish

Answer 36

- angiogenic vessels can be easily visualized in transparent zebrafish embryos - many mammalian regulators of angiogenesis have been found (VEGF, ang-2, ang-1) - gene knockdown in zebrafish generated phenotypes similar to mouse

Question 37

easily targets organ systems in zebra fish

Answer 37

CNS, liver kidney, heart, GI, pancreas