PGx and Drug discovery Flashcards
(23 cards)
Efficacy –>
Gene regulation –> ADME and PK/PD –> toxicology –> IND
Purpose of Preclinical Studies
Establish safety
Predict potential toxicity
Provide rationale for studies in humans
Preclinical studies implication of data
ADME and toxicity info Safe for humans Data for continued use Data for larger pt population Determine impractical or unethical to investigate
Rats are used for
Cancer and toxicity
Monkeys are used for
HIV
Rabbits, guinea pigs and dogs are used for
CV
Preclinical studies Pharmacology Profile
Drug’s action on various animal systems
- MOA
- Dose response
- Duration of action
- Effects on major systems
- ADME
Preclinical studies Pharmacologic Screening
Determine any pharm action
- CNS, CV, ANS, Respiratory, GI, GU systems
In Vitro Pharmacology Study Properties
Stabiltiy
Solubility
Protein binding
Metabolism, cellular uptake, PK, PD
In Vitro Pharmacology Study Pharmacologic Effects on
Target sites Other systems Data analysis Implications - Can it be used to treat other conditions
Preclinical Studies Toxicity
Aids in deciding if the drug should be used in humans
Predict potential hazards
Subchronic toxicity data implication
2 weeks to 89 days MOA Activity Targets Dose response Sex differences
Chronic Toxicity Testing Protocol
3-12 months
1 rodent and 1 non
Multidose plus control
Carcinogenicity Testing Protocol
2 years
1 rodent and 1 non
Multi dose plus control
Major goal of PGx Research
Link biological response to different gene expression
Animal study groups
Vehicle study
Low dose
High dose
Purpose of Disease related animal model
Recognize subdivision of disease leading to better testing
ID biomarkers
ID disease mechanism
ID common links related diseases
Disease related animal model Acute Modulation
Short term
Transcription and translation
Disease related animal model Chronic Modulation
Transgenic (overexpression) Knock out (remove gene) Knock down (inhibit expression)
Primary cells
Difficult to obtain in large numbers
Irreversible growth arrest
Difficult to deliver drug
Antibody treatment
Knowledge of target required Multiple targets ADME issues Difficult to deliver Slow and time consuming Therapeutic potential
Types of Modulation of Protein Function
Dominant negative proteins
Aptamers
Zebrafish
Have lots of genes similar to humans
You can see organ development in these fish
