L13-14 Drug Discovery and Clinical Trials Flashcards Preview

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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