Overview Of Preclinical Research Flashcards
What are the 5Rs that are addressed in drug development?
Right target Right tissue Right safety Right patient Right commercial potential
What is the definition of a drug target?
A drug target is one that a molecule binds to produce a desirable effect
What are the main aims of pre-clinical/animal studies?
To provide information on safety and efficacy of a drug candidate before testing in humans
What are in-vivo studies?
Experiments inside an inside living organism
What are in-vitro studies?
Experimentations outside an organism in test tubes
What are ex-vivo studies?
Experimentations of intact tissues/organs outside a living organism.
What are in-silico studies?
Experimentations using computer simulation.
What are some advantages of in-vitro procedures?
High throughput screening = screening of known compounds from libraries
Reduced cost
Less regulations
Give examples of in vitro tests.
Cell line based training
- cell biology
- mechanism of action
- toxicology
Give an example of in-vivo testing and its use.
Small animals
- For complex disease mechanisms
- Overall effects on intact living organisms
- Effect of other organ systems
- Pharmacokinetics
- Safety
- Mandatory before human testing
What are the disadvantages of in vivo testing?
Highly regulated
Low throughput
What is a cell line?
Is a permanently established cell culture that will proliferate indefinitely given appropriate fresh medium and space.
What is the purpose of using in-vitro cell lines?
- Studying physiology, pathology and cell growth
- Alterations in the structure, function and genetic makeup of the cell under controlled environments
What is the disadvantage of in-vitro cell lines?
Not reflective of the biology of living organisms
What are the limitations of animal in-vivo models?
Not able to model all aspects of human disease
Even long term animal models are relatively short-term compared to the course of human disease
Species differences in biology
Animal studies have limited genetic diversity and they are carried out under controlled environmental conditions
What are the 3Rs of animal research?
Replace - animal studies with non-animal studies
Refine - minimise stress of study animals
Reduce - as few animal studies as required and necessary
What are the limitations of in vivo studies?
Results have limited replicability in humans
Due to:
Interspecies differences
Environmental stimuli - lab conditions may differ from natural environment
What is a genome?
An organisms complete set of DNA
What is genomics?
Study of the Genome, including Gene–gene and gene-environment interactions
Where can new drug targets be found?
Genomics & bioinformatics
Genetics - human mutation data linked to disease
Phenotypic arrays
Clinical precedent - information from existing drugs
What is genetics?
Hereditary
What is epigenetics?
Heritable changes in gene expression without changes to genome
What is bioinformatics?
An interdisciplinary science of storing, retrieving and analysing large amount of biological information
What is pathway analysis?
Finding out if the differentially expressed genes are associated with a certain biological process/molecular function.
How are drug targets found through genetics?
Human mutation data linked to disease
Phenotype studies for finding drug targets.
In vivo and in vitro phenotypic models
Neutralising antibodies/ gene knockdown
Clinical compounds/ drugs
Clinical precedent in discovery of drug targets.
Through information from existing drugs
What are the 2 steps in target validation?
Reproducibility of drug-target effect
Confirming drug-target effect
What is lead generation?
Identify drug compounds to bind to a target that is validated.
High throughput screening using compound libraries
What is high throughput screening?
HTS is a large compound libraries screened against an isolated target in a system.
What is fragment screening?
Screening of small fragments of compounds to pick up low affinity binding sites that can be built upon
What is rational subset screening?
Identification of chemical family/class known to hit target to increase hit rate Modification of existing active molecules through the knowledge of pharmacokinetics and toxicology
What are the aims of safety pharmacology?
Early detection & elimination of hazards
Risk assessment before first in human studies
Risk management and mitigation during clinical development
What is on-target toxicity?
Toxicity related to the primary mechanism of action.
For example; if a drug is designed to affect GPCR, this would result in the drug hitting the G protein too hard
What is off-target toxicity?
Toxicity is not predicted
= secondary affects
Drug has secondary affects on calcium channels for example.
Causing cardiovascular and neurological disorders
