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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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


3 common targets for drugs

Receptors, enzymes, transport proteins


How is lead finding carried out

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


How are libaries of millions of closely related molecules created

Combinatorial chemsitry


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


What are the 2 safety steps for lead selection

Exploratory toxicology
Exploratory safetyl


What is looked at in an exploratory toxicology

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


What is looked at in an exploratory safety

Off target binding profile
Prelim CV safety
Prelim CNS safety


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


What is used to test CV safety invitro

Arrythmia biomarker - hERG K channel
When this is blocked causes long QT syndrome


How is the explorarotry safetly in vitro tested

Repeated administration of the drug for 14 days
Histopathology of every tissue is then examined


What two regulatory studies are carried out during pre clinical testing

Regulatory toxicology
Regulatory safety


What is looked at during a regulatory toxicology

General toxicity


What is looked at during a regulatory safety

Respiratory effects
CV safety
CNS safety


Stages for a safety pharmacology for a small molecule

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


Stages for a safety pharmacology for a biomolecule

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


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



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


What else must be carried out for a small molecule

Route specific studies
4.5-5 years

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


What is uncommon with a biomolecule

Cant cross the BBB so off target toxicology is uncommon


What are the immunotoxicology for a biomolecule

Thorough understanding required to understand the risk
Infusion reaction/ cytokine storm/ immunosuppresion/ autoimmunity


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


What would be looked at for clinical pathology

Haematology/ clinical chemistry
Kidney and liver function


What would be looked at for pathology

Large organ toxicity
Which organs are affected


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


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


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


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)


What methods of DNA damage may a drug do

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


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