L13-14 Drug Discovery and Clinical Trials

Question 1

Basic stages for a new drug to make it to the market

Answer 1

Basic research and target selection
Pre clinical research
Clinical development (3 phases)
Regulatory review

Question 2

3 common targets for drugs

Answer 2

Receptors, enzymes, transport proteins

Question 3

How is lead finding carried out

Answer 3

Automated screens against libraries, high throughput screen against the human gene in vitro
Screens should be fully automated

Question 4

How are libaries of millions of closely related molecules created

Answer 4

Combinatorial chemsitry

Question 5

Describe the processes involved with lead selection

Answer 5

Optimisation of the molecule 
Improve target specificity 
Improve potency 
Test for pharmaceutical and pharmacokinetic properties 
Reduced safety liabilities

Question 6

What are the 2 safety steps for lead selection

Answer 6

Exploratory toxicology

Exploratory safetyl

Question 7

What is looked at in an exploratory toxicology

Answer 7

General toxicity in silico and in vitro
Preliminary genotoxicity
Preliminary toxicity in vitro

Question 8

What is looked at in an exploratory safety

Answer 8

Off target binding profile
Prelim CV safety
Prelim CNS safety

Question 9

How is mutagenicity tested for in vitro during exploratory studies

Answer 9

Amnes test

Salmonella (his -) engineered to not be able to grow without histamine - if it is able to grow then mutation has occured

Question 10

What is used to test CV safety invitro

Answer 10

Arrythmia biomarker - hERG K channel

When this is blocked causes long QT syndrome

Question 11

How is the explorarotry safetly in vitro tested

Answer 11

Repeated administration of the drug for 14 days

Histopathology of every tissue is then examined

Question 12

What two regulatory studies are carried out during pre clinical testing

Answer 12

Regulatory toxicology

Regulatory safety

Question 13

What is looked at during a regulatory toxicology

Answer 13

Genotoxicity
Toxico/pharmacokinetics
General toxicity

Question 14

What is looked at during a regulatory safety

Answer 14

Respiratory effects
CV safety
CNS safety

Question 15

Stages for a safety pharmacology for a small molecule

Answer 15

1,3,6 month studies
Range finding studies
Developmental toxicity

Question 16

Stages for a safety pharmacology for a biomolecule

Answer 16

1,3,6 month studies
Range finding studies
Developmental toxicity studies

Question 17

Are the safety pharmacologies for a small molecule and biomolecule the same

Answer 17

YES

Question 18

What animal tests must be carried out for a small molecule (animal toxicology)

Answer 18

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

Question 19

What else must be carried out for a small molecule

Answer 19

genotoxicology
carcinogenicity
Route specific studies
4.5-5 years

Immunotoxicology
Often unexpected and off target
Indicators: Haematol changes/ immunosupp / autoimmunity

Question 20

What is uncommon with a biomolecule

Answer 20

Cant cross the BBB so off target toxicology is uncommon

Question 21

What are the immunotoxicology for a biomolecule

Answer 21

Thorough understanding required to understand the risk

Infusion reaction/ cytokine storm/ immunosuppresion/ autoimmunity

Question 22

What are the goals of non-clinical safety evaluations

Answer 22

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

Question 23

What would be looked at for clinical pathology

Answer 23

Haematology/ clinical chemistry
Kidney and liver function
Coagulation

Question 24

What would be looked at for pathology

Answer 24

Large organ toxicity

Which organs are affected

Question 25

What happened with the TGN1412-CD28-SuperMAB trial

Answer 25

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

Question 26

Describe how a CVS system safety would be carrier out

Answer 26

In vitro electrophysiology to screen for QT prelongation (hERG assay) In vivo assesment of QT - non rodent CV telemetry

Question 27

Describe how a CNS safety would be carried out

Answer 27

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

Question 28

Describe how a genetic toxicology test would be carried out

Answer 28

Mix of in vitro and in vivo designed to detect compounds that induce genetic damage Using a Amnes test (for his- salmonella)

Question 29

What methods of DNA damage may a drug do

Answer 29

Gene mutation Chromosomal damage Recombination chromosomal changes Prediction of potency for malignanacy of genetic effection

Question 30

How would the metabolism of a drug be tested

Answer 30

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

Question 31

What conclusions need to be made before clinical development is able to proceed

Answer 31

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

Question 32

What was the issue with Elixir Sulfanllamide

Answer 32

Contained diethylene glycol - killed 107

Question 33

What was the issue with sulfrathiazole tablets

Answer 33

Tainted with sedative phenobarbital | Numerous control deficiencies

Question 34

What was the issue with Thalidomide

Answer 34

First synthesised in 1954 | Launched as a sleeping tablet but caused birth deformations

Question 35

Phase 1 trials

Answer 35

Is it safe (how much reaches target/minimal dose) How well is it tolerated Pharmacokinetic properties Small no. healthy volunteers

Question 36

Phase 2 trials

Answer 36

How much should be given for it to be effective How well does the treatment work Not blind

Question 37

Phase 3 trials

Answer 37

``` 1000s of patients Definitive results Multicentre and multinational Application for marketting Randomised and double blind studies ```

Question 38

Regulation is by

Answer 38

Independent organisations

Question 39

Phase IV trials

Answer 39

Post marketting surveillance Detect rare/long term adverse effects Also applies to medical devices Helps with the directing of the labelling

Question 40

How many drugs that enter this process make it to market

Answer 40

11%