Decision making in pre-clinical development Flashcards
What are the Factors to Consider in Target ID?
Validation -
• Are drugs hitting this target likely to be efficacious? – Human validation – Preclinical validation
Feasibility -
• Are we likely to be able to make drugs which hit this target? – “Drugability” – Screening – Safety liabilities
Portfolio Fit -
• Are we the right people to make drugs which hit this target? – Competitive Landscape – Portfolio shape (Low risk, low prize vs high risk, high prize)
Target Validation is almost never a binary decision. TRUE OF FALSE?
TRUE
What is the process for Traditional “biased” target validation?
- Target Biology
- Genetic variation
- Phenotype
What is New generation –omics-based “unbiased”
target validation?
- Phenotype
- Genetic variation
- Target Biology
What are the Major Components of Target
Validation for human data?
- Clinical Experience
- Genetic Linkage
- Tissue Expression
What are the Major Components of Target
Validation for preclinical data?
- Translational Endpoints
- Pharmacology
- Genetically Engineered Models
Large ligands have high potential potency, – but many more ways to clash with the active site, – likely to be unable to ‘express’ innate binding
functionality even when close to desired
pharmocophore. True or False?
TRUE
Small ligands have a higher probability of
binding – actives will be found, but may bind weakly – “Fragment Screening. TRUE OR FALSE?
TRUE
Name the different Characteristics of Drug Candidates
Potency Selectivity Toxicity Absorption Excretion Metabolism Absorption
Name Lipinski’s Rule of 5
5 or fewer H-bond donors
10 or fewer H-bond acceptors
Molecular weight less than or equal to 500
Calculated log P less than or equal to 5
“Compound classes that are substrates for biological
transporters are exceptions to the rule“
What is Disease-model Efficacy?
Models which replicate pathophysiology
found in human patients
Drugs which alter pathophysiology in man
have same effects in model. TRUE OR FALSE?
TRUE
What is High-dose PK/PD studies?
De-risk expensive regulatory toxicology studies –
(If single-dose studies cause issues then compound
unlikely to progress through pre-clinical development)
What questions need to be asked when Defining a Human Predicted Efficacious Dose for Clinical Trials?
- Is the dose achievable?
- Is there likely to be a therapeutic window?
- Is the dose commercially viable?
What is therapeutic window?
Is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.
