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Why you don’t need imaging to apply microdosing

Maarten Brom, PhD

Microdosing and molecular imaging studies often go hand in hand. By labeling your drug with a radionuclide or fluorescent dye you can study the on- and off-target binding of your drug. Even before the classical Phase I-IV clinical trials. But did you know that you can also use microdosing in different ways? Even without labeling and/or molecular imaging?

Accelerator Mass Spectrometry (AMS).

When you develop a drug, you want to know the pharmacokinetics (PK) and the metabolites of your drug in humans. With pharmacokinetics you can study the movement and interactions of drugs in the human body. The general method to measure PK and metabolites is to measure the drug and its metabolite in plasma (or blood, urine, and feces) by mass spectrometry. However, mass spectrometry is not sensitive enough to measure the drug concentrations used with microdosing.

Instead, you can use Accelerator Mass Spectrometry (AMS). AMS can measure very low concentrations of carbon-14 labeled drugs. So, when you label your drug with carbon-14, you can administer a microdose and measure the PK and metabolites in a Phase 0 study.

Intra-target microdosing technique.

Another way to use microdosing without molecular imaging is to administer a microdose to a certain tissue with a restricted volume or area. When you apply the microdose of your drug to this small area, you can achieve therapeutic doses. At the same time, the whole-body exposure is well under the microdose quantity. This method is also referred to as intra-target microdosing.

For example, when you administer a microdose of your drug directly in a tumor, you can achieve local therapeutic concentrations. Simultaneously, the systemic exposure is very limited. Implantable devices are being developed where you can fill the device with your drug and then implant it in the tumor where it releases the drug over a certain period. Of course, without exceeding the microdose. Afterwards, you can examine the antitumor effect of your drug in the resected tumor tissue. This allows you to test the therapeutic effect of your compound.

Besides tumors, this microdosing technique can also be applied to other tissues of interest. For skin diseases you could directly apply a microdose of your new drug on a small area of the diseased skin (i.e. topical administration). A biopsy and histology would then reveal the efficacy of your drug. You could also measure treatment response by ultrasound imaging or MSOT/RSOM.

It is also possible to apply intratarget microdosing in organs that are accessible by endoscopes or catheters. For example, you can apply a microdose of your drug in a small part of the lungs in respiratory diseases. Or you could administer a drug in the bladder in case of bladder cancer. Measurement of the efficacy of your drug would then take place by endoscopic imaging.

When to use which microdosing technique?

In short, your research questions determine which microdosing approach you should choose for your study. For example, microdosing in combination with molecular imaging give you information on the spatial distribution of your drug. This means you can follow its distribution over time. Also, it allows you to accurately quantify your labeled drug in organs and tissues.

Although with molecular imaging you can predict a potential therapeutic effect based on the on- and off-target uptake of your drug, you don’t get actual therapeutic efficacy data. This is possible when you use intra-target microdosing, as you then obtain local therapeutic efficacy data. However, as you administer the drug directly to the tissue of interest, you don’t know if your drug reaches the target with systemic administration. Intra-target microdosing studies are also useful for compounds that are difficult to label.

Microdosing studies with AMS only give you information on the pharmacokinetics. You can also use this method to measure bioavailability and target engagement: how much of your drug is available to reach the target and potentially have a therapeutic effect? AMS studies are also suitable for your selection of an optimal lead compound for clinical development.

Not sure which microdosing approach fits your clinical development goals best? Contact us for advice.

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