Exam 2 lecture 12 Flashcards Preview

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Flashcards in Exam 2 lecture 12 Deck (37):
1

preclinical testing, research & development time range

1-3 years
avg: 18 mo

2

clinical research & development time range

2-10 years
avg: 5 yrs

3

NDA review time range

2mo-7yrs
avg:24 mo

4

phase 1

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

5

phase 2

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

6

phase 3

clinical efficacy
(safety & population PK)

7

is phase 4 required?

no

8

purpose of preclinical studies

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

9

implication of preclinical data

- 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

10

animal commonly used to study HIV

monkey

11

animal commonly used to study CV

rabbits and dogs

12

animal commonly used to study toxicology & cancer

rates & mice

13

preclinical studies pharmacology profile

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

14

preclinical studies pharmacology screening

- to determine any pharmacologic action
-- CNS, CV system, autonomic nervous system, respiratory system, GI system, GU system

15

in vitro pharmacology study

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

16

in vivo pharmacology study

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

17

preclinical studies: toxicology

- 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

18

types of toxicology testing

acute
subchronic
carcinogenicity
reproduction & teratology
mutagenicity

19

subchronic toxicology data implication

MOA
pharmacologic activity
target organs
dose-response relationship
sex difference

20

chronic toxicity testing protocol

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

21

carcinogenicity testing protocol

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

22

reproductive & teratology testing

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

23

toxicogenomic approaches

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

24

disease research purposes:

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

25

acute modulation of target expresssion

transcription
translation

26

chronic modulation of target expression

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

27

what is the role of a protein in biological effects?

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

28

RNA interference (RNAi)

- 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

29

antibodies

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

30

modulation of protein function

- antibodies
- dominant negative proteins
- aptamers

31

animal models that should represent chronic diseases

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

32

animal models that should represent phenotypes

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

33

model organisms all to ID novel targets and pathways

drosophila
C. Elegans
zebrafish

34

mouse models

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

35

zebrafish

- 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

36

angiogenesis & zebrafish

- 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

37

easily targets organ systems in zebra fish

CNS, liver kidney, heart, GI, pancreas