100-200 Healthy subjects, to see if the drugs are safe for humans (pharmacokinetics)
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Phase II
200-300 Patients, does it work in patients
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Phase III
1,000- 3,000 Patients, does it really work in patients
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Phase IIIb
Patients, does it work in a different group of patients
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Phase IV
10-1,000 Patients, does it work in patients, compared with similar drugs
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In vitro tests for mutagenicity
Tests for mutations and the rate of mutations
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In vitro cytogentic evaluation
Tests for chromosome damage, looking for tumour development and damage in pregnant females
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Lethal dose (LD50)
The dose of drug which kills 50% of treated animals within a specified short amount of time.
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NOAEL
The highest concentration that does not produce a toxic response
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LOAEL
The lowest concentration that produces a toxic response
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HED
The does in humans anticipated to provide same degree of effect as observed in animals at given dose.
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Method for NOAEL
NOAEL -> HED -> Lowest HED-> apply 10-fold safety margin. 112mg in 70Kg man
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Therapeutic Index
The ration of the dose of the drug that produces an unwanted toxic effect to that producing a wanted therapeutic effect: LD50/ED50
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TI
Measure of drug safety, a drug with a small TI is less safe than a drug with a large TI
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Theophylline
Has a narrow therapeutic index drug. Plasma levels were monitored, caused adverse effects
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Need for toxicity testing
E.g Elixir Sulfanilamide. Causes a mass poising. TGN1412 designed to bind to CD28 protein activation, triggering a cytokine release. Causes serious side-effects.
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