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Pharmacogenetics > Exam 2 lecture 12 > Flashcards

Exam 2 lecture 12 Flashcards

1
Q

preclinical testing, research & development time range

A

1-3 years

avg: 18 mo

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2
Q

clinical research & development time range

A

2-10 years

avg: 5 yrs

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3
Q

NDA review time range

A

2mo-7yrs

avg:24 mo

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4
Q

phase 1

A

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

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5
Q

phase 2

A

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

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6
Q

phase 3

A

clinical efficacy

safety & population PK

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7
Q

is phase 4 required?

A

no

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8
Q

purpose of preclinical studies

A
  • 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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9
Q

implication of preclinical data

A
  • 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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10
Q

animal commonly used to study HIV

A

monkey

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11
Q

animal commonly used to study CV

A

rabbits and dogs

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12
Q

animal commonly used to study toxicology & cancer

A

rates & mice

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13
Q

preclinical studies pharmacology profile

A
  • MOA
  • dose response relationship
  • duration of action
  • effects on major systems
  • ADME
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14
Q

preclinical studies pharmacology screening

A
  • to determine any pharmacologic action

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

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15
Q

in vitro pharmacology study

A
  • 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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16
Q

in vivo pharmacology study

A
  • pharmacological effetcs
  • effects on target site/system
  • effects on other systems (animal model, readouts)
  • data analysis
  • implication in clinical trials
17
Q

preclinical studies: toxicology

A
  • 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
Q

types of toxicology testing

A 
acute
subchronic
carcinogenicity
reproduction & teratology
mutagenicity
19
Q

subchronic toxicology data implication

A 
MOA
pharmacologic activity
target organs
dose-response relationship
sex difference
20
Q

chronic toxicity testing protocol

A

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

21
Q

carcinogenicity testing protocol

A

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

22
Q

reproductive & teratology testing

A
  1. fertility & general reproductive performance
  2. teratology
  3. prenatal & postnatal study
23
Q

toxicogenomic approaches

A
  • link biological response to differential gene expression
  • animal study (3 groups- vehicle control, low dose & high dose treatment)
  • RNA microarray
24
Q

disease research purposes:

A
  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
Q

acute modulation of target expresssion

A

transcription

translation

26
Q

chronic modulation of target expression

A
  • transgenic approach aka knock-in(overexpression of target gene)
  • knock-out mice
  • knock-down approaches
27
Q

what is the role of a protein in biological effects?

A

increase activity» overexpression

decrease activity» inhibition (better model for drug action)

28
Q

RNA interference (RNAi)

A
  • 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
Q

antibodies

A
  • knowledge of target is required
  • multiple targets frequent
  • PK issues: ADME
  • difficult to deliver
  • slow & time consuming
  • therapeutic potential
30
Q

modulation of protein function

A
  • antibodies
  • dominant negative proteins
  • aptamers
31
Q

animal models that should represent chronic diseases

A

are difficult to model

e.g. COPD due to continuous exposure to smoke

32
Q

animal models that should represent phenotypes

A

are difficult to define & measure

e.g. psychiatry (schizo, depression)

33
Q

model organisms all to ID novel targets and pathways

A

drosophila
C. Elegans
zebrafish

34
Q

mouse models

A
  • transgenic
  • knock-in/knock-out
  • knock-down
35
Q

zebrafish

A
  • 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
Q

angiogenesis & zebrafish

A
  • 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
Q

easily targets organ systems in zebra fish

A

CNS, liver kidney, heart, GI, pancreas

Pharmacogenetics (8 decks)

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