Analysis from a clinical trial:
(1) For many drugs subjects will show a Gaussian distribution for dose vs effect (desired or toxic).
(2) Plot the dose to response curve, with X axis = dose and Y axis = cumulative percent of patients having a target response.
(3) Determine the point where 50% of subjects show the target response.
Parameters:
(1) effective dose 50th percentile (ED50) = dose associated with 50% of patients achieving desired effect
(2) lethal dose 50th percentile (LD50) = dose associated with50% of patients dying as a result of the drug
The use of a lethal dose as an endpoint is seen in animal studies. In human studies serious toxicity (toxic dose or TD) may be a more relevant endpoint.
therapeutic index =
= LD50 / ED50
Interpretation:
• The higher the therapeutic index, the less the risk of a fatal reaction during routine use of the drug.
• A drug with a small therapeutic index ("narrow") can cause serious complications if there is even a slight increase in drug accumulation (from higher dose or reduced elimination).
Limitations:
• This is only a measure of dose-related effects. Allergic or idiosyncratic reactions are independent of dose.
• Any overlap between the curves means that one patient could be having effective therapy at the same dose as someone else is experiencing a toxic reaction.
• The tighter the curve the better the 50th percentile reflects the particular dose.
