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BMS242 Core Phys Pharm > L13-14 Drug Discovery and Clinical Trials > Flashcards

L13-14 Drug Discovery and Clinical Trials Flashcards

1
Q

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

A

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

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2
Q

3 common targets for drugs

A

Receptors, enzymes, transport proteins

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3
Q

How is lead finding carried out

A

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

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4
Q

How are libaries of millions of closely related molecules created

A

Combinatorial chemsitry

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5
Q

Describe the processes involved with lead selection

A 
Optimisation of the molecule 
Improve target specificity 
Improve potency 
Test for pharmaceutical and pharmacokinetic properties 
Reduced safety liabilities
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6
Q

What are the 2 safety steps for lead selection

A

Exploratory toxicology

Exploratory safetyl

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7
Q

What is looked at in an exploratory toxicology

A

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

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8
Q

What is looked at in an exploratory safety

A

Off target binding profile
Prelim CV safety
Prelim CNS safety

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9
Q

How is mutagenicity tested for in vitro during exploratory studies

A

Amnes test

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

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10
Q

What is used to test CV safety invitro

A

Arrythmia biomarker - hERG K channel

When this is blocked causes long QT syndrome

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11
Q

How is the explorarotry safetly in vitro tested

A

Repeated administration of the drug for 14 days

Histopathology of every tissue is then examined

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12
Q

What two regulatory studies are carried out during pre clinical testing

A

Regulatory toxicology

Regulatory safety

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13
Q

What is looked at during a regulatory toxicology

A

Genotoxicity
Toxico/pharmacokinetics
General toxicity

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14
Q

What is looked at during a regulatory safety

A

Respiratory effects
CV safety
CNS safety

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15
Q

Stages for a safety pharmacology for a small molecule

A

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

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16
Q

Stages for a safety pharmacology for a biomolecule

A

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

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17
Q

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

A

YES

18
Q

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

A 
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
Q

What else must be carried out for a small molecule

A

genotoxicology
carcinogenicity
Route specific studies
4.5-5 years

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

20
Q

What is uncommon with a biomolecule

A

Cant cross the BBB so off target toxicology is uncommon

21
Q

What are the immunotoxicology for a biomolecule

A

Thorough understanding required to understand the risk

Infusion reaction/ cytokine storm/ immunosuppresion/ autoimmunity

22
Q

What are the goals of non-clinical safety evaluations

A

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
Q

What would be looked at for clinical pathology

A

Haematology/ clinical chemistry
Kidney and liver function
Coagulation

24
Q

What would be looked at for pathology

A

Large organ toxicity

Which organs are affected

25
Q

What happened with the TGN1412-CD28-SuperMAB trial

A

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
Q

Describe how a CVS system safety would be carrier out

A

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

27
Q

Describe how a CNS safety would be carried out

A

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
Q

Describe how a genetic toxicology test would be carried out

A

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

29
Q

What methods of DNA damage may a drug do

A

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

30
Q

How would the metabolism of a drug be tested

A

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
Q

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

A

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
Q

What was the issue with Elixir Sulfanllamide

A

Contained diethylene glycol - killed 107

33
Q

What was the issue with sulfrathiazole tablets

A

Tainted with sedative phenobarbital

Numerous control deficiencies

34
Q

What was the issue with Thalidomide

A

First synthesised in 1954

Launched as a sleeping tablet but caused birth deformations

35
Q

Phase 1 trials

A

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

36
Q

Phase 2 trials

A

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

37
Q

Phase 3 trials

A 
1000s of patients 
Definitive results 
Multicentre and multinational 
Application for marketting 
Randomised and double blind studies
38
Q

Regulation is by

A

Independent organisations

39
Q

Phase IV trials

A

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

40
Q

How many drugs that enter this process make it to market

A

11%

BMS242 Core Phys Pharm (9 decks)

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