Lecture 9 - drug development and discovery 1 Flashcards
Key stages of drug development
- basic research and target selection
- pre-clinical research
- clinical research (phase 1,2 and 3)
- regulatory review
what is the target selection for drugs?
includes receptors, enzymes and transport proteins
what is lead finding?
- finding the lead compounds of the drugs by cloning target protein in human form
what is primary screening?
used to prepare sets of homologues by combinational chemistry to identify structural features for selective binding to the target
Exploratory safety measures (lead selection)
- predicting safety concerns by selecting a candidate
- this helps in the next steps towards study designs
Regulatory safety measures (preclinical and clinical)
- provides a safety margin
- defines dose to start human trials and the max dose
- obtain regulatory approval of clinical
What is LD50
experiment conducted in mice to determine the dose of a chemical that causes 50% death rate called median lethal dose.
common rodent study
rat because it is easier to manipulate and has greater blood volumes
common non-rodent study
beagle because it has consistent quality of health and low background pathologies
what are the three dose groups for toxicology study?
- low (no toxicology)
- intermediate
- high (toxicology expected in target organ)
clinical pathology
- haematology/ clinical chemistry
- kidney and liver function
- coagulation
what is histopathology?
- studying structural manifestation of disease under a microscope where these results are one of the most important parts on non-clinical safety measurements.
what is pathology?
- large organ toxicity
- determining which organs are affected
goal of preliminary toxicology?
tests eliminates genotoxicity and determines the non-toxic dose of the drug.
goal of pharmacokinetic testing?
includes studies of absorption, metabolism, distribution and elimination in lab animals
what does chemical and pharmaceutical development assess?
feasibility of large-scale synthesis and purification. assess stability of the compound under various conditions to develop a formula suitable for clinical studies
what happens in the phase 1 clinical trial?
- tests if the drug is safe to humans and checks for any potential problems in physiological systems.
- sees if drug produces any unpleasant symptoms and pharmacokinetic properties
- conducted on small group of healthy volunteers
what are the smaller groups within a clinical trial called?
cohorts
- first cohort given a small dose of the drug and dose adjusted for other groups
where is phase 1 clinical trial conducted?
done in labs to investigate if the drug is hitting its target or changing at the level of a protein.
looks into how the drug will interact with other drugs or food
what happens in phase 2?
- tested on 100-300 patients to test the efficacy in clinical situation and then establish a dose used for phase 3
- these studies cover several distinct clinical disorders to identify possible therapeutic indications for new compound.
what happens in part 2 (part a)?
- exploratory study that has clinical efficacy
- tests pharmacodynamics or biological activity
- explores dose range
- conducted on patients or healthy volunteers
what happens in phase 2 (part b)
- more definite dose range study in patients
- efficacy as the main focus
- used as pivotal trials for drugs treating life-long illnesses
what happens in phase 3?
- double-blind and randomised trial
- performed on thousands of patients to compare the new drug with an alternative.
- these are very expensive to organise
what happens in phase 3 (part a)?
- designed and executed to get statistically significant evidence of efficacy and safety as required by world organisations.
- includes post marketing study commitments
- presents data to the regulatory agencies to decide if drug is approved.
what happens in part 3 (part b)
- study prior to approval with intended support of publications rather than registration
what happens in phase 4?
- obligatory post marketing surveillance to detect any rare or long-term side effects from using drug in clinical environment for thousands of patients
- could limit use of drug in certain groups
withdrawing drugs
- to do with risks of patients or commercial reasons
- risks or harms is the main reason with unexpected side effects that were not detected
