Therapeutic Index & Therapeutic Window

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Quantal Response Curves

Quantal: Binary ("either-or" or "all-or-none") responses. Specify 50% and 100%, which we'll see are important

Let's imagine we want to know the minimum dose required to achieve a systolic blood pressure of less than 120 mg Hg. The response we are examining is binary: is the individual's blood pressure less than 120 or not. What we really want to determine is: for the average individual what dose of drug will be required to drop blood pressure below 120. Imagine we’re testing in a large population of people.

A small percentage of people require just 1 mg of drug to achieve a systolic BP of less than 120 mmHg and an increasing percentage of people require higher and higher doses to achieve this until we reach a midpoint at which time a decreasing number of people require a further increasing doses of drug.

This data fits underneath a bell-shaped curve; it fits a normal distribution.
We show a sigmoidal curve for the cumulative percentage of people that exhibit the desired therapeutic effect at increasing dose of medication. This curve reaches 100% at the right-side of the corresponding bell-shaped curve.

ED50

At the peak of the bell-shaped curve, the corresponding dose is the ED50: the median effective dose.

ED50 refers to the dose at which 50% of people will achieve the specified effect: it’s the effective dose for 50% of the population.
It answers our original question, in the average person, what dose of drug do we expect is required to achieve a systolic BP less than 120 mmHg.

TD50 & LD50

We can also ask the question, however, what dose is too high? Meaning, what dose is toxic or lethal to the average individual?

Here, we label the 50% point as TD50: the dose at which 50% of people will achieve a toxic effect. LD50 refers to lethality; the LD50 is the dose at which 50% of people will die from medication.
Thus, TD50 or LD50 refers to the dose at which 50% of people experience Toxicity or Lethality.

Therapeutic Index & Therapeutic Window

Therapeutic Index

What we want to clinically is how much room do we have to "play" with the drug dosing – what’s a safe but also effective range to work with?

The therapeutic index is an important ratio to determine how close a toxic dose is to an effective one. Note that the term therapeutic index is often used more loosely, not just in these formulatic terms, and is often conflated with the therapeutic window, which we'll define soon.

Therapeutic Window

Whereas with our therapeutic index, we were thinking in terms of drug dose (ED50 and TD50 were based on drug dose); here, we are thinking about the blood concentration of the drug: the drug level.
The minimum effective concentration (MEC) represents the minimum blood level necessary to achieve a specified biological effect.
The minimum toxic concentration represents the minimum blood level at which a toxic effect occurs.
The range between these two values represents the therapeutic window.

The therapeutic window is the range of blood level wherein the drug is producing the desired effect without the feared toxicity.

For reference, the United States Food & Drug Administration (FDA) uses the term "narrow therapeutic index" for drugs that have a less than twofold difference in LD50 and ED50 or MTC and MEC.

Example

Consider a seizure drug, for example, that requires a concentration of 15 mcg/mL to control seizures but causes aplastic anemia at a concentration of 25 mcg/mL.
This drug would be considered to have a narrow therapeutic index. It may be effective in treating seizures but it is all too easily toxic to the bone marrow.