Flashcards in L13-14 Drug Discovery and Clinical Trials Deck (40)
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1
Basic stages for a new drug to make it to the market
Basic research and target selection
Pre clinical research
Clinical development (3 phases)
Regulatory review
2
3 common targets for drugs
Receptors, enzymes, transport proteins
3
How is lead finding carried out
Automated screens against libraries, high throughput screen against the human gene in vitro
Screens should be fully automated
4
How are libaries of millions of closely related molecules created
Combinatorial chemsitry
5
Describe the processes involved with lead selection
Optimisation of the molecule
Improve target specificity
Improve potency
Test for pharmaceutical and pharmacokinetic properties
Reduced safety liabilities
6
What are the 2 safety steps for lead selection
Exploratory toxicology
Exploratory safetyl
7
What is looked at in an exploratory toxicology
General toxicity in silico and in vitro
Preliminary genotoxicity
Preliminary toxicity in vitro
8
What is looked at in an exploratory safety
Off target binding profile
Prelim CV safety
Prelim CNS safety
9
How is mutagenicity tested for in vitro during exploratory studies
Amnes test
Salmonella (his -) engineered to not be able to grow without histamine - if it is able to grow then mutation has occured
10
What is used to test CV safety invitro
Arrythmia biomarker - hERG K channel
When this is blocked causes long QT syndrome
11
How is the explorarotry safetly in vitro tested
Repeated administration of the drug for 14 days
Histopathology of every tissue is then examined
12
What two regulatory studies are carried out during pre clinical testing
Regulatory toxicology
Regulatory safety
13
What is looked at during a regulatory toxicology
Genotoxicity
Toxico/pharmacokinetics
General toxicity
14
What is looked at during a regulatory safety
Respiratory effects
CV safety
CNS safety
15
Stages for a safety pharmacology for a small molecule
1,3,6 month studies
Range finding studies
Developmental toxicity
16
Stages for a safety pharmacology for a biomolecule
1,3,6 month studies
Range finding studies
Developmental toxicity studies
17
Are the safety pharmacologies for a small molecule and biomolecule the same
YES
18
What animal tests must be carried out for a small molecule (animal toxicology)
1 year non rodent
Rodent and non rodent
Using a rat and beagle
With 3 dose groups
1) low - no toxicity
2) Intermediate
3) High toxicity expected
19
What else must be carried out for a small molecule
genotoxicology
carcinogenicity
Route specific studies
4.5-5 years
Immunotoxicology
Often unexpected and off target
Indicators: Haematol changes/ immunosupp / autoimmunity
20
What is uncommon with a biomolecule
Cant cross the BBB so off target toxicology is uncommon
21
What are the immunotoxicology for a biomolecule
Thorough understanding required to understand the risk
Infusion reaction/ cytokine storm/ immunosuppresion/ autoimmunity
22
What are the goals of non-clinical safety evaluations
Toxicity (on/off target + reversibility)
Toxicokinetics (relate toxicity to exposure)
MAX non toxic dose
Min effective dose
Dose selection for first in human
Identification of specific monitoring requirements
23
What would be looked at for clinical pathology
Haematology/ clinical chemistry
Kidney and liver function
Coagulation
24
What would be looked at for pathology
Large organ toxicity
Which organs are affected
25
What happened with the TGN1412-CD28-SuperMAB trial
It is a monoclonal AB against T cell receptors which switch them ON
Dose given was 500 times lower than toxic dose
Volunteers suffered a cytokine storm (ess. an allergic reaction throughout the body)
Put 6 in hospital
Caused by a change in a single amino acid which was not picked up
26
Describe how a CVS system safety would be carrier out
In vitro electrophysiology to screen for QT prelongation (hERG assay)
In vivo assesment of QT - non rodent CV telemetry
27
Describe how a CNS safety would be carried out
Irwin observation of 3 dose levels and a control and observe:
Physical factors and gross appearance
Observation of behaviours in novel environments
Reflexes and reactions to simple stimuli
Grip strength, motor coordination and locomotor action
28
Describe how a genetic toxicology test would be carried out
Mix of in vitro and in vivo designed to detect compounds that induce genetic damage
Using a Amnes test (for his- salmonella)
29
What methods of DNA damage may a drug do
Gene mutation
Chromosomal damage
Recombination chromosomal changes
Prediction of potency for malignanacy of genetic effection
30
How would the metabolism of a drug be tested
In vitro - liver cells on 96 well plate
In vivo - looking for a species specific metabolite, if metabolite accounts for >10% of the parent compound compound - major metabolite - may have to resynthesise and retest
31
What conclusions need to be made before clinical development is able to proceed
evidence of pharmacological activites
Max non toxic dose
Adverse effects of target organs
Relationship of effects to dose and exposure
Differences that may be observed in different species
EVALUATION OF RISK IN HUMANS
32
What was the issue with Elixir Sulfanllamide
Contained diethylene glycol - killed 107
33
What was the issue with sulfrathiazole tablets
Tainted with sedative phenobarbital
Numerous control deficiencies
34
What was the issue with Thalidomide
First synthesised in 1954
Launched as a sleeping tablet but caused birth deformations
35
Phase 1 trials
Is it safe (how much reaches target/minimal dose)
How well is it tolerated
Pharmacokinetic properties
Small no. healthy volunteers
36
Phase 2 trials
How much should be given for it to be effective
How well does the treatment work
Not blind
37
Phase 3 trials
1000s of patients
Definitive results
Multicentre and multinational
Application for marketting
Randomised and double blind studies
38
Regulation is by
Independent organisations
39
Phase IV trials
Post marketting surveillance
Detect rare/long term adverse effects
Also applies to medical devices
Helps with the directing of the labelling
40
