Exposure v. Safety Margins

Welcome back to Tox & Trials, a newsletter that gives you a first-hand, raw, educational view of toxicology in the pharmaceutical industry.

Did you know exposure margins and safety margins are actually two very different things?

Sometimes, these terms are used interchangeably but they really shouldn’t be. They both have very distinct use cases and using one for the other or vice versa can cause significant regulatory issues.

Let’s break it down:

Exposure Margin

An exposure margin is the margin between the exposure for which an adverse effect (or the NOAEL) is seen in animals and the anticipated (or measured) human exposure.

For example, say you run a rat study and see liver toxicity at AUC = 8,000 hng/mL. Through computer modeling, you anticipate your human exposure will be AUC = 2,000 hng/mL. Your exposure margin then comes out to be 8,000/2,000 = 4, which means that you have a 4x exposure margin of toxicity for that target organ over your anticipated human exposure.

Another example is if you run a rat study and your NOAEL comes out to 50 mg/kg with an associated AUC of 10,000 hng/mL. Through computer modeling, you anticipate your human exposure will be AUC = 1,000 hng/mL. Your exposure margin then comes out to be 10,000/1,000 = 10, which means you have a 10x exposure margin for your study.

For translating toxicology studies to the clinic, exposure margins are very important. They can tell us how critical an adverse effect is or how important a target organ may be. If you have liver toxicity at 4x over your anticipated human exposure, like in the example above, this means that at some point between 0x and 4x the human exposure there is a toxicological threshold in the rat. That threshold becomes more and more “safe” the greater your exposure margin may be, for example, if it was 10x. The greater your exposure margin, the better safety profile you have going into the clinic.

Safety Margin

A safety margin is the margin between the dose for which toxicity occurs in animals and the dose which is therapeutic in the human.

For example, you run a rat study and your NOAEL comes out to 50 mg/kg. Through modeling, you anticipate your human therapeutic dose to be 10 mg/kg. Your safety margin then comes out to be 50/10 = 5, which means that you have a 5x safety margin between your animal studies and your anticipated human studies.

Notice how the safety margin specifically refers to comparisons of dose, rather than drug exposure. You can see why we use exposure margins in toxicology versus safety margins, because safety margins only give us one piece of the puzzle whereas exposure margins dig a little deeper into the story.

Here is a visual, obviously, that you may or may not have seen before:

Use Cases

The use of one over the other depends on several factors, but in general we would use exposure margin in an IND when discussing any toxicity or adverse effects we see in animals that we want to ensure are covered in FIH trials. For safety margins, we might use these when correlating assay data or in vitro work to show the translation into the clinic.

In addition, when we are using exposure or safety margins in drug development, there are certain ranges that we need to reach. For example, if you are developing an oncology drug, your exposure margin of toxicity can be as low as 1x. However, if you are developing a non-oncology drug then your exposure margin would most likely need to be 10x. Certain exceptions to this can be made based on scientific justification, of course.

One the best things to do is to look up approved drugs that have the same or similar MOA as your drug on Drugs@FDA. From here, you can see the Sponsor’s entire nonclinical development program, the data and most importantly, what the FDA reviewer had to say about it. Many times they will state whether they agreed or disagreed with the Sponsors position, including the exposure and safety margins, and if they disagree they will say why. This can be invaluable information for your programs especially if you’re margins are coming out a bit lower than expected.

And that, my friends, is the difference between exposure and safety margins!

Until next time!

Dessi McEntee is a board-certified toxicologist with extensive experience in bringing new medicines to the clinic and beyond through well-executed nonclinical development programs and strategy. She delivers Tox & Trials in an effort to help educate on the nuances of navigating nonclinical safety and toxicology within drug development, a commonly misunderstood or under-understood piece of the pharmaceutical pipeline.