Are you ready for your GLP toxicology studies? Not without dose range-finding studies, you aren’t. Here are 3 reasons why these can’t be skipped.
A well-planned preclinical toxicology program always starts with the end in mind. In the case of dose levels, then, you probably have an idea of your ideal range based on the exposure you want to achieve in clinical. For some drug developers, especially those new to the industry, it’s exciting, and tempting, to jump right into GLP studies: one step closer to your IND filing.
But that’s not a great idea.
Even if you have disease model studies from other species, or historical tests from years ago with a new formulation or different route of administration, or you can back into an effective dose based on your drug compound’s chemistry – proper dose range-finding studies, while not strictly required for your IND filing, are a must.
To understand why, here’s a quick review of what they tell you.
What Are Dose Range-Finding Studies?
Non-GLP dose range-finding (DRF) studies help drug developers select the appropriate doses for later pivotal regulatory studies.
By administering varying dose levels to different species and closely monitoring for adverse effects, drug developers can identify a range of dose levels for GLP pivotal studies. The high dose level selected is usually the maximum tolerated dose (see Figure 1 of ICH Guideline M3R2); low and middle doses are often successive half-log intervals of the high dose. For example, if your high dose is 100 mg/kg, low and mid doses are 10 and 30 mg/kg, respectively. DRF studies are needed to help determine your maximum tolerated dose.
Why Do You Need Dose Range-Finding Studies?
#1. Inform GLP Toxicology Studies
Dose range-finding studies are an essential precursor to pivotal studies:
- Single dose acute toxicity studies identify potential adverse effects of the new drug candidate.
- Repeat dose chronic toxicity studies evaluate the effects of repeat administration over a defined period of time.
Unless your clinical plan is only a single dose, your pivotal, or IND-enabling, study will more often than not be a repeat dose study for 14-28 days. This study is critical to your IND approval and requires a robust protocol, an experienced laboratory that will generate and interpret quality data, and GLP compliance. Because of the rigorous standards for GLP pivotal studies it’s important to have the best data available informing your study design before you initiate the GLP study. Dose range-finding studies are how you get there.
#2. Understand Your Drug Compound Even More
Dose range-finding studies help you learn a lot about your drug beyond just dose level.
For example, when you take blood samples to look at the pharmacokinetics (PK) of the drug in the animals, you can correlate signs of toxicity to the drug levels and kinetics and better design the timing of in-life parameters in your GLP study.
Look for signs of toxic effects using the following parameters:
- Body weights
- Clinical observations
- Clinical chemistry
- Coagulation parameters
- Neurological observations (for neurological drugs)
- Cytokines (for immune-stimulating drugs)
- Flow cytometry (for immunomodulatory drugs)
Ultimately, dose range-finding studies present an excellent opportunity to learn more about your drug so you’re ready for GLP and IND filing. Use this as a chance to get the most information as possible so you can create a robust GLP study.
#3. Prevent Costly Repeat GLP Studies
Toxicology studies that result in too much toxicity or none at all are not ideal. If your doses are too high, you may not have a NOAEL (No Observable Adverse Effect Level) that is used to calculate your starting dose on the clinic. If you have no toxic effects at all, and can demonstrate sufficient exposure, you may have to use a maximum feasible dose approach to assign a high dose (see again ICH M3R2 Figure 1). Dose range-finding studies can be repeated until you find the appropriate dose and route of administration. This is much more cost effective than repeating a GLP study.
Every robust drug development program should include dose range-finding studies before moving to GLP toxicology studies.
However, a good rule of thumb when planning your toxicology program is to ask these questions about your drug compound, especially when it has been tested in other programs:
- Has this compound been tested in animals before?
- Has this compound been tested in the species that will be used in toxicology studies?
- Is the formulation the same?
- Is the dose level range the same?
- Is the planned route of administration the same?
“No” to any of these questions means you should take the step to perform a dose range-finding study. Ultimately, it’s very important to have recent and reliable data in the relevant toxicology species before you commit to a GLP study. You should be confident in your toxicity levels. In a perfect world, you will have tested your drug compound in the same facility, same species, with the same circumstance to generate baseline data before you move forward with GLP.
Whether you’re still in early discovery or getting ready for IND submission, toxicology testing is a substantial part of drug development. A laboratory testing partner can help you manage your timelines, plan the right studies, and meet regulatory requirements.
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