Drug development Flashcards
What are the 5 stages of developing a new drug?
1) Basic research to target selection
2) Pre-clinical research
3) Clinical development
4) Regulatory review
5) Postmarketing surveillance
What does basic research to target selection lead to?
The identification of a target through basic understanding of the disease
Eg. it is known that inhibiting a certain receptor has a certain effect - makes sense to look for antagonists of this receptor
What occurs in pre-clinical research?
Evaluation of drugs in animal models
What occurs in clinical development?
3 phase testing of the drugs in human patients
What are the most common drug targets?
Enzymes
Receptors
Transport proteins
How is a lead target found?
Use the lead target to find the lead compound:
- Clone the lead target
- Using an assay, test many compounds, to test the functional activity of the target (eg. enzymatic activity if the lead target is an enzyme)
- Normally use AUTOMATED screens, which test all the compounds in a chemical library
What is a chemical library?
Why are they used in lead compound selection?
A library of molecules created by combinatorial chemistry:
- Creating MANY compounds which are all related to a ‘parent’ compound
Used in lead compound selection as the different compounds have slightly different shapes/properties
Therefore one may fit better into the lead target
What process is done after the lead compound is selected?
LEAD OPTIMISATION
What is the need for lead optimisation?
1) Improve target specificity (reduced side effects?)
2) Improve potency
3) Improve pharmaceutical and pharmocokinetic problems
(look at potential problems of what the drug may metabolise into)
4) Reduce safety liabilities
What do the steps in pre-clinical development aim to test?
1) Genotoxicity
2) Regulatory safety evaluations
3) Non-clinical safety evaluations
4) Pharmacokinetics
5) General toxicology and animal toxicology
What is genotoxicity?
Testing the destructive effects of the drug on the cells genetic material
What is tested when testing the regulatory safety of a drug?
If the drug has any obvious behavioural effects and effects on the:
1) Respiratory system
2) CV system
3) CNS
Why can the same prediction methods not be used for small molecules and biomolecules?
- Biomolecules have different properties to small molecules
- Many post-translational modifications occur on biomolecules when they are synthesised and this can impact how they are handled in the body
What do biomolecules break-down into?
Why is this advantageous?
Amino acids by proteases
No toxic metabolites
Which takes longer to test: small molecule drugs or biomolecules?
Why?
Small molecules:
- Must test carcinogenicity, genotoxicity etc (doesn’t already exist in the body)
What are the goals of non-clinical safety evaluations?
1) Time duration of the drug
2) Metabolic affects
(May produce inactive version - stay around for longer)
3) Toxicity
(Reversibility, on/off target)
4) Toxicokinetic
(toxicity to exposure)
5) Max non-toxic dose/ min affective dose
6) Dose selection for first in humans
7) Identification of specific monitoring requirements
What is the general toxicology testing?
Pathology:
Haematology
Changes in immune system
Kidney/liver function
Coagulation
Large organ toxicology
Describe animal toxicology testing, when relating to SMALL MOLECULES?
- Use rodents and non-rodents (beagle)
Three dose groups tested:
- Low (non-toxic)
- Intermediate
- High (toxicology expected in target organ)
What are the differences between small molecules and biopharmaceuticals?
Biopharmaceuticals:
- Proteins from the body which are enhanced and used as drugs
Small molecule drugs:
- Synthetic (man-made) drugs which MIMICK the effect of endogenous compounds OR from biological PLANT material
Is off-target toxicology common in biopharmaceuticals?
Why?
No
They are broken down into NON-TOXIC amino acids
They do not enter cells
What animal models are used for testing biopharmaceuticals?
Non-human primates
What are the adverse reactions that can be caused by biopharmaceuticals? Describe them (2)
1) Exaggerated pharmacology
- May have higher specificity than expected
- Therefore, stronger reaction
2) Anti-drug antibody reaction
- May have accelerated clearance
- May have prolongation of exposure
- May neutralise the pharmacological activity
With which type of drug is there often rare and unexpected off-target?
Small molecule
What are the immunotoxicology risks of small molecule drugs?
1) Haematological change
2) Weight change
3) Infection of spleen, lymph node (histopathy - changes in tissues do to disease)
What are the immunotoxicology risks of biopharmaceutical drugs?
1) Infusion reaction (fever, chills etc)
2) Cytokine storm (organ failure)
3) Immunosupression (leave animal vunerable to other diseased)
4) Autoimmunity
What must be concluded before testing drugs in humans?
- Evidence of activity
- Maximum non-toxic dose
- Adverse effects on target organs
- Relationship of effects to dose and exposure
- Differences observed in different species
- Evaluation of risk in humans
When testing drugs on humans, what dose are they tested with?
Dilutions LESS than the lowest dose tested in animals
Who is tested in phase I of clinical trials?
Small number of HEALTHY volunteers (20-50)
What are the questions answered in phase I of clinical trials?
1) Is the drug safe
2) Is the drug well tolerated (nausea, vomiting, headache etc)
3) What are the pharmacokinetic properties?
(fully accountable throughout body, exert all response)
Who and how is tested in phase II of clinical trials?
NOT blind test on more volunteers (100-500) who HAVE the disease
What are the questions answered in phase II of clinical trials?
1) How much should be given to be effective?
2) How well does the treatment work?
Who and how is tested in phase III of clinical trials?
Randomised DOUBLE BLIND tests on 1,000-5,000 volunteers:
- Multi-centre (different hospitals)
- Multi-national
- Patients with OTHER conditions
What might phase III of clinical trials show?
Individual variance
What happens in the regulatory approval stage?
- Look at ALL of the data
- Scrutinised by regulatory agencies all over the world, who don’t work together (drug may be accepted by one but not another)
- Look at value for money
When testing biomolecules, in the pre-clinical stage, what must be looked at?
Pharmacokinetics (broken down into amino acids)
Immunogenicity (rejection)
