How many phases are there in drug development?
4: I, II, III, IV
List 3 questions that are asked in Phase I of drug development
- What does the body do to the drug? (pharmacokinetics)
- What does the drug do to the body? (pharmacodynamics)
- Does it seem safe in humans?
What is the Ames test used for?
In vitro test for mutogenicity
What happens during an Ames test
Salmonella bacteria are used as it can't synthesise histidine (amino acid)
- The salmonella bacteria are grown on histidine-containing media
- Drug is added to plate as well as a liver enzyme = cytochrome p450 (to test for reactive metabolites) - toxified or detoxified
- Histidine becomes depleted and only mutants which can cope without histidine can grow back
This measures the rate at which a drug induces mutations in bacteria
What does an Ames test measure?
The mutation rate = the rate at which a drug induces mutations in bacteria
A high mutation rate is undesirable - potentially mutagenic and carcinogenic
What occurs during carcinogenicity testing?
Chronic drug dosing, look for tumours
What occurs during reproductive (teratogenicity) testing?
Pregnant females from 1 rodent species and 1 non-rodent species (usually rabbit)
- Dosed with the drug at different organogenesis stages
- Look for birth defects
What is preliminary toxicity testing?
Maximum non-toxic dose is given to 2 species for 28 days
- Animals examined post-mortem and tissue damage assessed
The dose of drug which kills 50% of treated animals within a specified short amount of time
Measured in M
How is LD50 found?
Graph plotted of toxic response (%) vs Log[drug] (M)
= no observed adverse effects level
Highest concentration of drug that does not give any toxic effects
= lowest observed adverse effects level
Lowest concentration of drug that produces a toxic effect
How is the 'Human Equivalent Dose' found?
- Extrapolation from the NOAEL value
- Using a conversion table, based on body surface area (mg/m^2)
- Apply a >10 fold safety factor
Define: Human Equivalent Dose (HED)
The dose in humans anticipated to provide the same degree of effect as observed in animals at a given dose
Define: Therapeutic index
The ratio of the dose that produces an unwanted (toxic) effect to that producing a wanted (therapeutic) effect
How is the therapeutic index calculated?
The median effective dose = the effective dose for 50% of people recieving the drug
What is ED50 also known as?
EC50 = effective concentration
How is the therapeutic index of a drug affected when the ED50 and LD50 concentrations are very close?
Narrow therapeutic index - potentially dangerous drug e.g warfarin
How does the therapeutic window link to the therapeutic index?
Larger therapeutic window = larger therapeutic index
What is therapeutic index a measure of?