Prof VY In-vitro & In-vivo Methodologies in Preclinical Research Flashcards
Importance of GLP
Determine safety profile of the drug
Hence, it is only required for studies for determining safety, not so much for other types of studies
Documentation for GLP (2)
- high level of detailed documentation
- cost of documentation may exceed the cost of conducting the experiment
Confusion about GLP (2)
- Semantic (meaning directly from the word)
- not really about good laboratory practices but more about good documentation - Regulatory requirements of GLP
- not required for all studies but only for studies for determining safety
When is GLP used? (3)
- when studies are focused on safety
- during the final stage of preclinical development to obtain regulatory approval for IND
- before proceeding to clinical studies
When is GLP required? (3)
- when studies are focused on safety
- during the final stage of preclinical development to obtain regulatory approval for IND
- before proceeding to clinical studies
Disadvantages of GLP (4)
- Inflexibility
- plan each step & document it first then do what you document - Time-consuming
- heavy emphasis on documentation - High cost
- Scientific challenge
- most scientist do not have the experience working with GLP
CRO & their purpose (2)
Contract Research Organisation
- pharmaceutical companies to outsource their preclinical studies
- more cost effective
In-Vitro Methodology advantages (4)
- Cost
- cell models > animals - Efficiency
- shorter time for analysis - Availability of human-based cell models
eg iPSC - Suitable for in-depth mechanistic analysis
- analysis at molecular level
In-Vitro Methodology advantages (4)
- Cost
- cell models > animals - Efficiency
- shorter time for analysis - Availability of human-based cell models
eg iPSC - Suitable for in-depth mechanistic analysis
- analysis at molecular level
In-Vitro Methodology disadvantage (1)
Unreliable for predicting pharmacological & toxicological responses in intact animal
- complex biological systems in humans come into play
Applications of In-Vitro Methodology in preclinical studies (2)
- ADME
- toxicology
FDA requirements for preclinical research (3)
- Pharmacological profile of the drug
- Acute toxicities on at least 2 species
- Short term toxicities
- ranging from 2 weeks - 3 months
Applications of In-Vivo methodology in preclinical studies (2)
- determine dosage levels to be used in clinical trials phase l
- toxicology
Commonly used animal models in preclinical studies (2)
- Canine
2. Murine
NOEL
No Observable Effect Levels
- highest dose that produce no noticeable toxic effects
Why is the use of animal testing reduced in recent years? (3)
- High cost
- Ethical issues
- Long experimental period
Limitations of In-Vivo animal testing in preclinical studies (4)
- High cost
- Ethical issues
- Long experimental period
- Distinct toxicity response in human not picked up by animals
Clinical implication of
- Organ selective toxicity in preclinical studies : +ve
- Organ selective toxicity in humans : -ve
Loss of potentially efficacious drug
- once preclinical studies show +ve for toxicity, pharmaceutical companies may discontinue drug development
Clinical implication of
- Organ selective toxicity in preclinical studies : -ve
- Organ selective toxicity in humans : +ve
Risk of causing toxicity in humans after drug development & marketing
- lead to higher financial loss to pharmaceutical companies
Type of error when
- Organ selective toxicity in preclinical studies : +ve
- Organ selective toxicity in humans : -ve
False +ve
Type of error when
- Organ selective toxicity in preclinical studies : -ve
- Organ selective toxicity in humans : +ve
False -ve
Methods in conducting In-Vivo studies on toxicity (acute)
- LD50 (traditional method)
- dose which result in 50% animal death - Modified LD50 (modern method)
- dose which result in some death
- conducted on 2 rodent species - “Fixed dose” method
- if >90% survival, increase dose by 10x
- if <90% survival, decrease dose by 10x
Types of classification of toxicity (4)
- Very toxic
- dose reduction but still <90% survival - Toxic
- dose reduction leading to >90% survival - Harmful
- dose increment leading to <90% survival - Unclassified (slightly toxic)
- dose increment but still >90% survival
Method in conducting In-Vivo studies on toxicity (chronic) (1)
Repeat administration of the drug
Effect of tumour promoter vs tumour initiator
Tumour promoter
- size of tumour increase but no. of tumours remains unchanged
Tumour initiator
- no. of tumours increase but size of tumours remains unchanged
Distinct toxicity response in human meaning (3)
Ways to overcome it (1)
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
Distinct toxicity response in human meaning (3)
Ways to overcome it (1)
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
Xenobiotics
- foreign chemicals introduced into the body system
