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
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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
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animal commonly used to study HIV
monkey
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animal commonly used to study CV
rabbits and dogs
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animal commonly used to study toxicology & cancer
rates & mice
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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
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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
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in vivo pharmacology study
- pharmacological effetcs
- effects on target site/system
- effects on other systems (animal model, readouts)
- data analysis
-implication in clinical trials
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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
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types of toxicology testing
acute
subchronic
carcinogenicity
reproduction & teratology
mutagenicity
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subchronic toxicology data implication
MOA
pharmacologic activity
target organs
dose-response relationship
sex difference
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chronic toxicity testing protocol
duration: 3-12 months
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use
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carcinogenicity testing protocol
duration: 2 years
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use
observation: cancerous growth
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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
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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
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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
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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
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mouse models
- transgenic
- knock-in/knock-out
- knock-down
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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
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