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Microdosing with and without molecular imaging

Milou Noltes, MD, PhD

Microdosing can provide you with in vivo data on pharmacokinetics, pharmacodynamics, and mechanism of action early in your drug development process. Often this information is retrieved through a combination of microdosing and molecular imaging. But microdosing does not always need imaging.

What is microdosing?

Microdosing is a technique that you can use to study the behavior of your drug in humans. In general, you do this by administering a microdose into your target population. A microdose is a dose so low that it has no therapeutic effect, but is high enough to study its cellular response. The FDA and EMA define a microdose as a maximum of <100ug (<30 nmol protein) or 100x lower than the therapeutic dose.

Microdosing and molecular imaging.

The low exposure levels used in microdosing require sensitive methods to detect your drug and its effects in humans. A common way to do this is with nuclear or fluorescent molecular imaging. These imaging modalities can simultaneously visualize the therapeutic compound and biological processes at the cellular level.

To visualize your drug with molecular imaging you need to label it with a fluorescent dye or radionuclide. These labels can visualize your compound when activated with a specific light source for fluorescence or by detecting photons emitted by a radionuclide using a PET scan.

When you combine microdosing and imaging, you can identify appropriate therapeutic targets, evaluate on- and off-target effects of candidate drugs, assess dose-response, and evaluate your drug’s biological biodistribution and pharmacodynamics/kinetics.

Microdosing without molecular imaging: intra-target microdosing.

Alternatively, you can use intra‐target microdosing (ITM). ITM is a drug development tool that combines features of microdosing and intra-target drug delivery.

In this case your drug is locally administered. This causes the therapeutic-level exposure only to be in a small proportion (about 1/100th) of the total body mass. Then when your drug enters the systemic circulation it is diluted (about 100-fold) such that the resulting systemic concentration is sub-pharmacological. In other words, a microdose.

The initial exposure of the target organ to pharmacological concentrations enables you to gather early, safe, and inexpensive detection of safety‐ and efficacy‐relevant biomarkers and pharmacokinetic data with minimal risk. In IMT, you can directly study the outcome of your drug in the target tissue without the need for labelling your drug.

Intra-Target Microdosing in lung cancer.

As such, Tsai (2022) and colleagues have developed an implantable microdevice for drug screening in patients with non-small cell lung cancer (NSCLC). This microdevice was placed into NSCLC tumors of patients undergoing resection, remained in situ during the surgery, and was retrieved in the excised specimen. Subsequently, they show histopathological and proteomic comparative analysis of drug effects of multiple therapies in the NSCLC with minimal morbidity and no systemic toxicity. Using this technique, they can observe and evaluate how an individual patient’s tumor cells respond to up to 20 different chemotherapeutic agents at one time using microdoses to minimize systemic exposure and risk.

ITM will not be applicable to all developmental scenarios. However, if it is, you do not always need molecular imaging to detect your drug and its effects in patients. Although pharmacokinetic data in the tissue of interest can additionally be obtained as in conventional microdose studies, thereby maximizing the informative data from a single study. For example, via PET imaging.


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