Advanced microtracer studies

Efficient drug development

A drug’s absorption, distribution, metabolism, excretion (ADME), and Adverse Drug Reactions (ADRs) are often difficult to predict. At TNO we have developed in vitro and ex vivo platforms that can help to make this easier. In combination with our in vitro microbiome platform and our Accelerator Mass Spectrometer (AMS) platform, we have a wide range of tools for predicting and measuring ADME/DMPK (Drug Metabolism and Pharmacokinetics) in human subjects, at an early stage. Some of these platforms can be used in the preclinical phase of drug development, and others in the clinical phase.

Pre-clinical ADME/DMPK in human subjects

Drug transport

Within the broad spectrum of DMPK research, TNO has an extensive range of tests for drug transport, including a test that measures protein levels. We offer transport tests (including regulation-based tests) on human subjects and rodents (CaCo-2, MDCK and HEK293).

Plasma Protein Binding (PEB)

The degree to which drugs bind to plasma proteins (pdf)  has a major impact on their pharmacokinetic properties. Numerous methods have been described for determining the free fraction of a drug in blood plasma. However, these do not meet the need for an extremely sensitive PEB test for hydrophobic and strongly binding drugs. We have developed a Comp3 test (‘competitive partitioning to a polymer phase’) for these types of substances. The results of the ComP3 test are highly reproducible (test sensitivity: free fraction in human plasma <0.05%).

I-screen, an in vitro intestinal microbiome platform

I-screen (pdf) can be used to investigate the ways in which substances affect the microbiota in the human intestine (and vice versa). I-screen employs physiological and anaerobic conditions to facilitate microbiota-based investigations of drug metabolism in the human intestine.

InTESTine, an ex vivo intestinal tissue model

InTESTine™ (pdf)  can be used to investigate the absorption, interaction, and translocation of pharmaceutical agents, biological substances, and nutrients in the intestinal wall. This physiological throughput system can accommodate fresh, ex-vivo intestinal mucosal tissue of human or animal origin, so it closely resembles the in vivo situation.

Ex vivo liver

In vitro liver models are generally unable to predict pharmacokinetics (PK). For this reason, TNO has developed an ex vivo liver platform (pdf)  that uses perfused livers from pigs and from human subjects with non-alcoholic steatohepatitis (NASH). This platform can be used to investigate the following processes:

  • bile secretion
  • liver clearance & metabolism
  • DDIs
  • analysis of safe liver function

ADME data at an early stage in clinical trials

TNO has access to two Accelerator Mass Spectrometers (AMS), which enable it to perform microdosing and microtracer studies. A minute quantity of the 14C-labelled drug is administered to volunteers or patients, after which the drug and/or its metabolites are measured in a range of different matrices (blood, plasma, urine, feces). The use of AMS technology, coupled with automatic sample combustion, can provide data on a drug’s absorption, distribution, metabolism and excretion at an early stage of clinical development.

Microdosing and AMS studies

A combination of microdosing and AMS can be used in an early preclinical phase (phase 0) to select drug candidates, based on their PK characteristics. To this end, it is sufficient to administer just a single microdose (<100ug, <1uCi) to volunteers or patients.

Microtracer and AMS studies

The use of microtracing does not require any changes to be made to the regular development process. It is simply added to the existing range of standard studies, to avoid delays in development. A classic phase 1 study – the oral administration of a cold therapeutic dose – may be extended to include the intravenous (IV) administration of a 14C microtracer at Tmax (the average time the drug takes to reach its maximum plasma concentration), to generate absolute bioavailability (‘AbsBA’) at an early stage of development. Additional microtracer studies (pdf)  will then provide mass balance data and Metabolite in Safety Testing (MIST) data, accelerating clinical development on the one hand, and making it less risky on the other.

Would you like to find out more about our ADME data collection activities, or, perhaps, cooperate with us? If so, then please get in touch with Steven Erpelinck.

Get inspired

10 resultaten, getoond 1 t/m 5

Time setters: reduce long waits for new medication with AMS

10 August 2023

In this episode, we talk to time setter Wouter Vaes, researcher in microdosing and microtracer studies, about using AMS technology to speed up the development time of new drugs by years.

Ex vivo organ perfusion provides accurate drug development data

14 March 2023

TNO uses ex vivo normothermic organ perfusion to more accurately determine ADME processes for specific compounds and accelerate drug development.

TNO helps accelerate drug development through insight

14 November 2022

To find the most effective interventions for complex metabolic diseases, we must first understand the dynamics of disease onset and progression. Only then can key targets and optimal therapeutic windows for more effective treatment be defined. We spoke with Anita van den Hoek, Research Scientist for TNO Metabolic Health, about how TNO helps pharmaceutical companies accelerate drug development through better understanding of disease pathways.

TNO proves method for effective pediatric drug development

14 November 2022

Safe and effective drug dosing for young children come with their own challenges. Up to the age of 18, a child’s metabolism can change significantly. And in the first two years of life, those ontogenic differences can be rapid and dramatic. TNO published its findings from the first drug disposition (mass balance/metabolite profiling) study to conclusively prove that microtracing with accelerator mass spectrometry (AMS) is an effective way to collect clinical data in these young patients. This AMS technology can also be the key to building up more data on drug interventions in pregnant and lactating mothers.

Functional microbiome analysis


TNO has a wide range of available tools to increase understanding of the impact and interaction of the microbiome on human health. Learn more.