PGx and Drug Discovery Flashcards
Preclinical drug evaluation
Design drug –> In vitro down-regulation studies –> In vitro culture/ assays –> In vitro pharmacology (ADME) –> In vivo down-regulation studies –> In vivo pharmacology (ADME) –> toxicology –> IND
Phase I
testing for safety
NOT LOOKING AT EFFICACY
initial PK/PD response
Phase II
looking at efficacy and more PK
Phase III
try to reproduce Phase II (and some Phase I)
Further confirmation the drug is safe and effective
Mice are used for:
cancer testing and toxicology testing
Primates are used for:
HIV and vaccine testing
Rabbits are used for:
cardiovascular testing
Pharmacology screening
have to screen several major systems that commonly have toxicity Regardless of class of drug, you have to do screening for all!
Why do we use animal models in PGx studies?
- recognize subdivisions
- identify biomarkers for human trials
- identify disease mechanisms
- identify common links between diseases (ex. obesity and HTN)
acute modulation of target expression
Study gene expression in short term; quick response; can be used for trauma studies/ infection
chronic modulation of target expression
• Transgenic approach= insert the gene to animal genome and create an animal with specific gene
○ AKA knock-in
• Knock-out= delete gene of interest at genetic level
• Knock-down= several approaches to remove some gene expression in some part
○ Only use epigenetic or RNA tech to inhibit expression and not completely remove it
Disadvantages of using primary cells in in vitro testing
Harder to get larger numbers
Harder to maintain in lab
Stopped in terms of growth (not going to grow once removed from body) and hard to deliver genes into
Antibodies
difficult to deliver and slow/ time consuming
What are some diseases that can’t use animal models?
COPD (mice don’t smoke) and psychiatric disorders (phenotypes are difficult to define and measure)
