What is "therapeutic index"

The therapeutic index (TI) (also referred to as therapeutic window or safety window or sometimes as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

Classically, in an established clinical indication setting of an approved drug, TI refers to the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.

In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population ( LD) divided by the minimum effective dose for 50% of the population ( ED). Today, more sophisticated toxicity endpoints are used.

$\mbox{Therapeutic Index} = \frac{\mathrm{LD}_{50}}{\mathrm{ED}_{50}}$ in animal studies, or for humans, $\mbox{Therapeutic Index} = \frac{\mathrm{TD}_{50}}{\mathrm{ED}_{50}}$

For many drugs, there are severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect.

Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.

Term

Meaning

'ED'

Effective Dose

'TD'

Toxic Dose

'LD'

Lethal Dose

'TI'

Therapeutic Index

'TR'

Therapeutic Ratio