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EPI PR3144 > Prof VY In-vitro & In-vivo Methodologies in Preclinical Research > Flashcards

Prof VY In-vitro & In-vivo Methodologies in Preclinical Research Flashcards

1
Q

Importance of GLP

A

Determine safety profile of the drug

Hence, it is only required for studies for determining safety, not so much for other types of studies

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2
Q

Documentation for GLP (2)

A
  • high level of detailed documentation

- cost of documentation may exceed the cost of conducting the experiment

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3
Q

Confusion about GLP (2)

A
  1. Semantic (meaning directly from the word)
    - not really about good laboratory practices but more about good documentation
  2. Regulatory requirements of GLP
    - not required for all studies but only for studies for determining safety
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4
Q

When is GLP used? (3)

A
  • when studies are focused on safety
  • during the final stage of preclinical development to obtain regulatory approval for IND
  • before proceeding to clinical studies
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5
Q

When is GLP required? (3)

A
  • when studies are focused on safety
  • during the final stage of preclinical development to obtain regulatory approval for IND
  • before proceeding to clinical studies
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6
Q

Disadvantages of GLP (4)

A
  1. Inflexibility
    - plan each step & document it first then do what you document
  2. Time-consuming
    - heavy emphasis on documentation
  3. High cost
  4. Scientific challenge
    - most scientist do not have the experience working with GLP
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7
Q

CRO & their purpose (2)

A

Contract Research Organisation

  • pharmaceutical companies to outsource their preclinical studies
  • more cost effective
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8
Q

In-Vitro Methodology advantages (4)

A
  1. Cost
    - cell models > animals
  2. Efficiency
    - shorter time for analysis
  3. Availability of human-based cell models
    eg iPSC
  4. Suitable for in-depth mechanistic analysis
    - analysis at molecular level
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9
Q

In-Vitro Methodology advantages (4)

A
  1. Cost
    - cell models > animals
  2. Efficiency
    - shorter time for analysis
  3. Availability of human-based cell models
    eg iPSC
  4. Suitable for in-depth mechanistic analysis
    - analysis at molecular level
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10
Q

In-Vitro Methodology disadvantage (1)

A

Unreliable for predicting pharmacological & toxicological responses in intact animal
- complex biological systems in humans come into play

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11
Q

Applications of In-Vitro Methodology in preclinical studies (2)

A
  • ADME

- toxicology

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12
Q

FDA requirements for preclinical research (3)

A
  1. Pharmacological profile of the drug
  2. Acute toxicities on at least 2 species
  3. Short term toxicities
    - ranging from 2 weeks - 3 months
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13
Q

Applications of In-Vivo methodology in preclinical studies (2)

A
  • determine dosage levels to be used in clinical trials phase l
  • toxicology
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14
Q

Commonly used animal models in preclinical studies (2)

A
  1. Canine

2. Murine

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15
Q

NOEL

A

No Observable Effect Levels

- highest dose that produce no noticeable toxic effects

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16
Q

Why is the use of animal testing reduced in recent years? (3)

A
  1. High cost
  2. Ethical issues
  3. Long experimental period
17
Q

Limitations of In-Vivo animal testing in preclinical studies (4)

A
  1. High cost
  2. Ethical issues
  3. Long experimental period
  4. Distinct toxicity response in human not picked up by animals
18
Q

Clinical implication of

  • Organ selective toxicity in preclinical studies : +ve
  • Organ selective toxicity in humans : -ve
A

Loss of potentially efficacious drug

- once preclinical studies show +ve for toxicity, pharmaceutical companies may discontinue drug development

19
Q

Clinical implication of

  • Organ selective toxicity in preclinical studies : -ve
  • Organ selective toxicity in humans : +ve
A

Risk of causing toxicity in humans after drug development & marketing
- lead to higher financial loss to pharmaceutical companies

20
Q

Type of error when

  • Organ selective toxicity in preclinical studies : +ve
  • Organ selective toxicity in humans : -ve
A

False +ve

21
Q

Type of error when

  • Organ selective toxicity in preclinical studies : -ve
  • Organ selective toxicity in humans : +ve
A

False -ve

22
Q

Methods in conducting In-Vivo studies on toxicity (acute)

A
  1. LD50 (traditional method)
    - dose which result in 50% animal death
  2. Modified LD50 (modern method)
    - dose which result in some death
    - conducted on 2 rodent species
  3. “Fixed dose” method
    - if >90% survival, increase dose by 10x
    - if <90% survival, decrease dose by 10x
23
Q

Types of classification of toxicity (4)

A
  1. Very toxic
    - dose reduction but still <90% survival
  2. Toxic
    - dose reduction leading to >90% survival
  3. Harmful
    - dose increment leading to <90% survival
  4. Unclassified (slightly toxic)
    - dose increment but still >90% survival
24
Q

Method in conducting In-Vivo studies on toxicity (chronic) (1)

A

Repeat administration of the drug

25
Q

Effect of tumour promoter vs tumour initiator

A

Tumour promoter
- size of tumour increase but no. of tumours remains unchanged

Tumour initiator
- no. of tumours increase but size of tumours remains unchanged

26
Q

Distinct toxicity response in human meaning (3)

Ways to overcome it (1)

A

Meaning

  • in preclinical animal models, there is no toxicity demonstrated
  • in human clinical trials, there is toxicity demonstrated
  • due to difference in physiology & genetics of animals & humans

Ways to overcome it
- transgenic models

27
Q

Distinct toxicity response in human meaning (3)

Ways to overcome it (1)

A

Meaning

  • in preclinical animal models, there is no toxicity demonstrated
  • in human clinical trials, there is toxicity demonstrated
  • due to difference in physiology & genetics of animals & humans

Ways to overcome it

  • transgenic models
  • knock in human genes to form transgenic model to determine toxicology in rats
28
Q

Xenobiotics

A
  • foreign chemicals introduced into the body system

EPI PR3144 (24 decks)

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