ACCELERATE YOUR CLINCAL DEVELOPMENT
MICROTRACING WITH AMS TECHNOLOGY LEADS TO FASTER DRUG DEVELOPMENT
Clinical Microtracer Research with Accelerator Mass Spectrometer (AMS)
The development of new medicines is a costly and time consuming process. One way to increase the efficiency of drug development pipelines is by using microtracer dosing. Microtracing is an innovative technology in which very small quantities of substances are tested in humans at a very early stage of development. No more than 100 micrograms, or 30 nmoles for proteins, are administered. This is less than one hundredth of the expected therapeutic dose, a quantity that does not cause side-effects.
A movie is created to explain the AMS technology, please click right to view
AMS allows scientists to analyze microtracers at low (fg/ml) levels.
When analyzing the effects of minute doses, an extremely sensitive technology is required to trace the substance, such as an Accelerator Mass Spectrometer (AMS). However, in order to be measured by AMS, a compound needs to have a stable radio-isotope label- called a microtracer. AMS allows scientists to analyze microtracers at low (fg/ml) levels. TNO is the first and only organization on mainland Europe to have this machine commercially available for biomedical research. The behavior of new compounds in humans can be studied up to 1000 times more sensitive than by conventional methods such as LC-MS.
In the human body, microtracers are mostly absent. Compounds labelled with radioisotopes can be quickly identified, making them an ideal tool in drug development. TNO distinguishes several different applications for microtracer dosing in drug development.
Revolutionized sample preparation
TNO has the unique ability to fully automate blood, plasma, urine or fecal sample analysis by AMS, based on auto-combustion. This differs significantly from the standard graphitization-based approach. Auto-combustion sample preparation allows us to analyse more samples per day, ensures a faster turnover time, and is more economical because it is far less labour-intensive. It also eliminates the need for material recovery and reduces recovery time for human volunteers.
- Validated total carbon-14 count in 2μl plasma (LLOQ 0.65 mBq/mL) -
Application and Service
|Exploratory IND Phase-0||By applying microdosing, TNO can determine the fate of new medicines very early in drug development (Phase 0). We can measure the pharmacokinetics of a substance, and all together, this information makes it possible to determine whether or not the medicine is compatible with a patient-friendly dosing regimen. Since extensive pre-clinical research is scarcely needed to do a microdosing study, fewer lab animals need to be sacrificed before the compound can be used in humans. The main advantage of microdosing is that it supplies extra information, based on research in humans, to arrive at an optimal go-no go decision. Taken the results of the microdosing studies into account, the Phase 1 trials can be designed much more effectively. A typical microdosing study consists of approximately 4-6 volunteers per compound.|
|Metabolite in Safety Testing (MIST)
Information rich Phase-1 research
|During Phase-1, any microtracer study is a potential MIST study, which will present the entire human metabolite profile. TNO’s facility is unique with both High Resolution MS and AMS. Directly after chromatographic separation the flow is split, whereby one part is on-line coupled to a High Resolution MS for direct metabolite identification. Simultaneously fractions are collected for off-line total radio-activity quantitation by cAMS.|
|Absolute Bioavailability (ABA)
Information rich Phase-1 research
|Medicines are commonly administered to humans for the first time in Phase 1 trials, to obtain primary data on pharmacokinetics. We can help extract more information from that compulsory research stage by adding a microtracer intravenously on top of your ‘common’ Phase 1 study and including the AMS in the subsequent analysis. This way, we can measure how much of the substance is absorbed and thereby determine the absolute bioavailability.|
|BIOLOGICALS / BIOSIMILAR||Biologicals (and biosimilars) are an upcoming class of drug compounds, unfortunately with a relatively high failure rate during drug development. This is mainly caused by the lack of suitable preclinical models to study PK profiles. Microdosing offers the superior advantage to obtain human data for biologicals, prior to a Phase 1 study and after limited preclinical safety testing. The biological can be radio-labeled using carbon-14 or iodine-129. The first microdosing study with a biological therapeutic protein in humans demonstrated excellent dose- proportionality. In addition a microdose can be used as a safe starting dose of biotherapeutics for FIM studies. Obviously, not for all biotherapeutics dose-linearity between microdose and therapeutic dose is expected. In these cases microdosing in combination with in vitro and PBPK modelling can still be of high value to predict pharmacokinetics at the therapeutic dose.|
Investigational drug production
|- 14C labeling of API. Other isotopes: 26Al, 129I and 41Ca （can be done by either GMP or Non-GMP)
- Analytical method development and validation.
- Sample analysis (AMS、LC-hrMS, LSC, LLSC, Microbeta2), Traditional LC-MS/MS
Technologies with AMS and Microtracing (OPEN FOR PARTNERING)
|Pediatric Microdosing||・Paediatric Accelerator Mass sPectrometry Evaluation Research (PAMPER).
2010: Grant from Priority Medicines for Children Program.
・Pediatric microdosing: elucidating age-related changes in oral absorption to guide dosing of new formulations.
2011: Grant from Priority Medicines for Children Program in The Netherlands (ZonMW)
|Screening of Proteins, ADC, Peptides||・How to discriminate different Antibodies/ADC/Peptides in target tissue or plasma?
|Evaluation of ADC, Payload,||・ADC: Tracing of Payload (Linker, Warhead) in human body|
|Evaluation of Biosimilar, Biosimilarity||・Clinical trial (Phase 0) to determine PK.
・Expose Human volunteers to Approved Biologic and Biosimilar Simultaneously
|Efficacy||・Bone Remodeling with 41Ca, Osteoporosis application
・Metabolic Flux 1: Fatty acid acyl hydrolase (FAAH inhibitor)
□ Pediatric Microdose study of oral [14C] midazolam; simultaneous metabolic profiling and quantitation using hrMS and AMS,Poster at ESDPPP, May-2019
□ The Impact of early human data on clinical development, there is time to win. Drug Disovery Today, April 2016
□ MICROTRACING WITH AMS TECHNOLOGY LEADS TO FASTER DRUG DEVELOPMENT, Feb, 2019
□ Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages. Clinical Pharmacology, 2015
□ Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using AMS.
□ Human ADME and Studies with Radiolabeled Compounds: Phase I-IIa, White paper, PRA Health Science.
Clinical and Translational Science, Feb, 2016.
Microdosing and Other Phase-0 Clinical Trials; Facilitating Translation in Drug Development.
Clinical Pharmacokinetics, Aug, 2015.
To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetic
British Journal of Clinical Pharmacology, Jan, 2015
Observational infant exploratory [14C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis.
British Journal of Clinical Pharmacology, July, 2012.
Simultaneous oral therapeutic and intravenous 14C-microdose to determine the Absolute Oral Bioavailability of Saxagliptin and Dapagliflosin.