Drug development Flashcards
What are the stages of drug development? (4)
- Basic research and target selection
- Pre-clinical research
- Clinical research (3 phases)
- Regulatory review
What is pre-clinical research?
Animal testing
What is clinical research?
- Human testing
- Split into 3 phases
What is phase 1 of clinical research?
Testing on healthy human volunteers
What is phase 2 of clinical research?
Testing on patients with the disease
What is phase 3 of clinical research?
Larger trial (1000+ patients) testing on patients with the disease
What is target selection?
Selection of ‘lead molecule’ by screening a series of molecules for their interaction with your chosen target (receptor/enzyme etc.) and identifying one that could be therapeutically useful
What testing is done after the selection of a lead molecule? (2)
- Exploratory toxicology
- Exploratory safety
What is LD50?
- The amount of the drug which kills 50% of the animals in the trial
- Old method of animal testing
How is animal toxicology carried out?
- Drug must be tested in a rodent (rat) and non-rodent (beagle)
- Testing carried out in 3 dose groups
What are the 3 dose groups tested in animal toxicology?
- Low (no toxicology)
- Intermediate
- High (toxicology expected in target organ)
What parameters are looked at in animal toxicology? (4)
- Haematology
- Kidney and liver function
- Coagulation
- Large organ toxicity
What are the goals of non-clinical safety evaluations? (7)
- Identify on/off target toxicity
- Reversibility
- Relate toxicity to exposure
- Define a max non-toxic dose and a min affective dose
- Select the dose for human testing
- Identify specific monitoring requirements
- Identify potential undesirable effects on CV system/CNS/respiratory etc.
What is determined in phase 1 clinical trials? (3)
- Safety
- Tolerance
- Pharmacokinetics (how long the drug stays in the body etc.)
What is determined in phase 2 clinical trials? (2)
- Dose
- Efficacy
How are biopharmaceuticals different from small molecule drugs? (2)
- Small molecule drugs have low molecular weight and are chemically synthesised
- Biopharmaceuticals (e.g. proteins, monoclonal antibodies) have more complex structures and are derived from living organisms
How is animal toxicology different when testing biopharmaceuticals vs small molecule drugs? (4)
- Need to be careful when selecting an animal model because biopharmaceuticals are humanised proteins which could likely cause an immune response if given to an animal
- Sometimes non-human primates are used
- Off-target toxicology uncommon
- On-target toxicology can be massive
What are ADA responses? (4)
- Anti-Drug Antibody responses
- Organisms being tested with biopharmaceuticals need to be monitored for the production of antibodies against the biologic
- Could cause accelerated clearance, neutralise the activity, prolonged exposure etc.
- Important pre-clinical evaluation for biologics
What is the maximum dose defined as for biopharmaceuticals in preclinical studies?
10x the maximum that would be used in clinical trials (no point going past that point)
What is the phase 1 dose defined as for biopharmaceuticals?
Smallest possible dose that is expected to cause a biological effect
What immunotoxicology tests are done preclinically for biopharmaceuticals?
Determine the risk for a cytokine storm reaction before clinical testing
What immunotherapies have been developed? (2)
- Checkpoint inhibitors
- CAR-T cell therapy
What are checkpoint inhibitors?
Monoclonal antibodies which release a natural brake on the immune system to allow T cells to attack tumours
What is CAR-T therapy?
Engineer a patient’s own immune cells to recognise their specific tumour
