How do you decide what dose to start at in the human?

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

The time has come.

You’ve been 8 years deep in preclinical and nonclinical research, working your butt off to get to this point.

Your blood, sweat and a lot of your tears have finally commenced into this moment: FIH Clinical Trials.

The first time your drug will go into humans. The first time you get to see if it has potential to even be a drug. The first time the world will get a glimpse into what you’ve been working on and if your company could go the distance.

And you better hope that first dose is the definition of well-executed.

So let’s talk about how that goes down.

There are several ways to get to your first starting dose:

1. NOAELs
2. HNSTDs/STD10s
3. MABELs
4. BMD

BMD = benchmark dose, and although the BMD is typically more accurate than using the other approaches it is rarely used in drug development.

The other 3 approaches are your go-to’s.

NOAELs

NOAEL = no-observable-adverse-effect-level.

The NOAEL is the dose level for which there are no adverse effects. This dose level may have shown test article related effects but it didn’t show any adverse effects, whereas the dose above the NOAEL will have shown test article related effects that were considered adverse. Here is an example of what this might look like on a study:

At the end of the study, the NOAEL dose is determined and this is the dose used to calculate the maximum recommended starting dose (MRSD). Typically, there are two NOAELs - one from the rodent study and one from the large animal study. Once the MRSD is determined for each NOAEL, one needs to be chosen to be used. The most appropriate species to use can be based off several factors including ADME considerations, species translation to the human, sensitivity to toxicity, etc.

The MRSD is calculated by converting the NOAEL dose into a Human Equivalent Dose (HED) and then applying a safety factor. The most common approach is to determine the HED using body surface area (but know there are other ways such as using AUC) and the most historically used safety factor is 10. There is a nifty chart we use for HED conversion included in the FDA Guidance for estimating the MRSD :

And here is the equation:

NOAEL ÷ species conversion factor = HED → HED ÷ safety factor x human wt. = MRSD

In practice it looks like this:

Say our NOAEL in the dog is 20 mg/kg, if this is our chosen species then the MSRD = 60 mg:

The NOAEL approach is typically used for small molecule, non-oncology compounds.

HNSTD/STD10

HNSTD = highest non-severely toxic dose

STD10 = severely toxic dose in 10% of animals

The HNSTD/STD10 approach is used in anticancer compounds and it allows some wiggle room in the human starting dose, called the safe starting dose in oncology or SSD.

Anticancer compounds are:

→ toxic by nature

→ administered to patients in Phase I versus healthy volunteers

→ need to have an ethical SSD to dose patients at a level within the therapeutic window

The HNSTD is used for large animal studies and the STD10 is used for rodent studies.

Typically what happens is the animal tox studies are conducted and NOAELs are established like any other tox study. The toxicologist putting together the IND package then goes in and determines the HNSTD and the STD10 for each species based on the highest dose level that does not produce evidence of lethality, life-threatening toxicities or irreversible findings. Here is an example of what this might look like on a study:

Sometimes, the NOAEL = HNSTD/STD10 but typically it is higher.

Now, to determine the SSD the same process for NOAELs/MRSDs above is followed except the safety factor for large animals is 6 instead of the usual 10.

Here is the equation:

HNSTD/STD10 ÷ species conversion factor = HED → HED ÷ safety factor = SSD

In practice it looks like this:

Say our NOAEL in the dog is 5 mg/kg and the HNSTD is established at 20 mg/kg, then if this our chosen species the SSD = 120 mg:

You can see how with oncology, the starting dose is a little higher than when using the NOAEL to calculate. As stated above, this is necessary to ensure ethical dosing of cancer patients in clinical trials. Dosing a patient with advanced cancer at a dose that isn't effective is - to be blunt - cruel.

MABELs

MABELs = minimal anticipated biological effect level

The MABEL is typically used for biologics because these molecules are assessed more on pharmacological activity than pure toxicity, and therefore the starting dose in humans needs to be based on the minimum level for which the drug will have a pharmacological action on the target be it a receptor, antibody, etc. in order to de-risk any potential cytokine release or immunogenicity.

Calculating the MSRD based on the MABEL is not as cut and dry as using the NOAEL/HNSTD/STD10 approaches. Rather, MABELs are determined using a lot of computer modeling, biomarker data, and functional endpoints. There is no historical or universal method for determining the MABEL.

Here is a graph of an estimation of a MSRD based on a MABEL:

Summary

Hopefully, this gave some good insight into how nonclinical toxicology studies hold the clinical trials on their shoulders. If your tox study isn’t well-executed, it could lead to some serious risks when your drug is administered to humans based on dose estimations alone.

To help put this all into perspective, here is a chart summarizing the different methods for human starting doses:

Note, there will be some molecules that fall outside of these guidelines as every molecule is different and must be personalized to its own needs. Always be sure to do your research so you know the best approach to take in establishing a starting dose. And don’t be afraid to consult external resources such as myself, other consultants, the FDA, other guidances, papers, etc.

One of the worst things you can do is spend a ton of time and money progressing a compound to FIH clinical trials only to have it crash and burn because your starting dose was off the mark.

#doyourhomework!

⭕ Have you ever had any issues in determining human starting doses?

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.