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The preclinical work before your Phase 0 imaging study

Maarten Brom, PhD

What preclinical work needs to be done before initiating a Phase 0 imaging study? A Phase 0 imaging study shows the pharmacokinetics (PK) and biodistribution (BD) of your compound. In other words, it shows whether the drug is on-target and where off-target distribution can cause side effects. What preclinical work before your Phase 0 imaging study needs to be done? This article tells you about it and helps you prepare for your Phase 0 clinical trial.

Phase 0 vs preclinical studies in large animal models

You can determine the PK and BD in animal studies, but it doesn’t always predict the situation in humans/patients. Also preclinical studies in large animal (closer to humans) don’t always predict the human situation. However, these studies are often required before you can start a Phase 1 clinical trial. A Phase 0 clinical trial is however conducted directly in the patient population. This can replace preclinical studies in large animal models. Moreover, it provides you with more relevant confirmation before your Phase 1 trial. Several preparations are needed to ensure safety.

What are Phase 0 or preclinical trials conducted on?

Preclinical trials are always conducted on animal models. A Phase 0 clinical trial is always conducted in-human and with a subtherapeutic dose. What is the purpose of Phase 0 clinical trial? The goal is to assess on- and-off-target accumulation of the drug in patients. There is much emphasis on patient selection because of the small number of participants. You’ll read more in-depth about patient selection later in this article.

Is Phase 0 the same as preclinical?

Phase 0 and preclinical are not the same, but do form a relation. There are reduced manufacturing and toxicologic requirements for Phase 0, but it doesn’t mean there are none. What is phase 0 of a project and what preclinical work needs to be done? Because the preparation may vary from project to project, we would like to get in contact. Contact us now for advice, or read the information below to get a general understanding.

What is NOT required for a Phase 0 study?

To start a Phase 0 imaging study, you don’t need dose escalation, safety after repeated dosing, and tolerance studies. Those come after the Phase 0 imaging study (pre-phase I study). You also don’t need clinical good manufacturing practice-grade (GMP) manufacturing of the precursor. What you do need is a good laboratory practices (GLP) product. Before you can start a Phase 0 study, some minimum laboratory studies (in vitro and small animal model studies) on toxicology and efficacy need to be done.

Preclinical study in vitro and in animal models before Phase 0 in-human trials

You need to do preclinical research in drug development to some extent. Depending on your drug, you need from preclinical study: in vitro experiments in cell lines that show biomarker binding and effect on target. You also need preclinical pharmacokinetic–pharmacodynamic relations. You will need positive and negative controls to show specific binding.

Preclinical study: rodent model

Retrieve in vivo PK/BD and targeting data in a rodent model expressing the target. This depends on your drug. For example, a mouse tumor model in the case of oncology. A Phase 0 study is however not limited to imaging. For studies using any form of extraction method a reliable SOP for tissue harvesting, handling, and processing is required. You need to simulate this in animal models before initiating Phase 0. At TRACER we specialize in Phase 0 molecular imaging. Even if you are not yet ready for Phase 0, contacting us will give you the information to exactly know what steps you need to take in each phase. This can prevent you from missing steps or spending resources on unnecessary research.

Preclinical work before Phase 0 imaging study: determine the dose

Before you can conduct a Phase 0 imaging study, you need to perform extended single-dose toxicity study in rodents. The used dose in Phase 0 studies may not exceed 100 microgram (max. 30 nmol for protein products) or 1/100th of the dose for pharmacologic effect. This number is derived from your calculated preclinical animal studies. Because of the dose, Phase 0 studies are often referred to as micro dosing studies or trace-dose human absorption. This brings us to the following, compound tracer conjugation.

Preclinical work before Phase 0 imaging study: compound tracer conjugation

Volunteers are given a single sub-pharmacological dose of a radiolabeled compound. At TRACER we are specialized in tracers. Our specialists will find the best suitable labeling strategy. We are the only Clinical Research Organization that works with both fluorescent dyes as radionuclides. We analyze your compound and discuss your research objectives. We then choose or develop the right label for your compound. With positron emission tomography (PET), single photon emission computed tomography (SPECT) and other ultrasensitive analytical tools we provide a detailed report of the pharmacokinetics and biodistribution of your compound.

Book your free Knowledge session with TRACER. From experience, we can tell what kind of tracer will match your compound.

Preclinical work before Phase 0 imaging study: participants

How many participants for a Phase 0 imaging study? In most cases 10-15 participants are sufficient. This is significantly less when you compare Phase 0 vs Phase 1 studies. Because of the small sample size, the selection of participants is very important. Patient should be selected for drug/target factors as well as to minimizing attrition. At TRACER we work closely with hospitals. Intra- and inter patient variability play a huge role.

Preclinical work before Phase 0 imaging study: mechanism of action

The subject of low toxicity is already evaluated with the extended single dose toxicity study. To study the mechanism of action with your Phase 0 study, you need preexisting information on molecular pharmacology from animal studies. To study the mechanism of action, one condition is that you develop a Phase 0 study that allows you to do so. As you might conclude from this, not every Phase 0 study is the same. It depends on your end points, your compound and existing variability in measurable data. After a successful Phase 0 study, you can go into the next phases of clinical trials with more knowledge.


Preclinical work ensures the safety of your Phase 0 study. It also provides you with the preclinical proof-of-concept. Therefore, it has its impact on the effectiveness of your Phase 0 study. Considerable preexisting information on the molecular pharmacology of your drug is required. The necessary preclinical work depends on your project. At TRACER we specialize in Phase 0 imaging studies. As an expert in this field, we provide Knowledge sessions for pharmaceutical, biotech and drug development companies.

Book your knowledge session now.

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