AMS microtracer studies let teams generate human ADME and mass balance data early in clinical development, while there is still time to act on the results. In a recent Clinical Pharmacology Podcast episode, Peregrion CSO Wouter Vaes explains how accelerator mass spectrometry supports lower-radioactivity 14C study designs and why moving these questions earlier can change downstream decisions.
Key takeaways
- AMS measures 14C atoms with very high sensitivity. Wouter describes at least 250x higher sensitivity than liquid scintillation counting for blood, plasma and urine samples, and up to 10,000x higher sensitivity for metabolite profiling.
- Lower 14C activity can make mass balance, metabolite profiling and absolute bioavailability questions easier to address in Phase 1 or Phase 2a settings, in accordance with ethics and regulatory requirements.
- A microtracer arm can often be integrated into an existing clinical trial, reducing the need for a separate late-stage human ADME study.
- Earlier human ADME data can inform on possible DDIs and the need for hepatic impairment or renal impairment studies, metabolite safety and formulation strategy before these issues reach the critical path.
- Oncology is a strong use case because early trials are usually conducted in patients, relative high dosing regimes are applied, co-medication is common, hepatic and renal impairments regularly occur among the target group, and metabolism data are often sparse.
What is an AMS microtracer study?
An AMS microtracer study administers a very small amount of 14C-labelled drug substance so drug-related material can be traced in human samples. Unlike liquid scintillation counting, which measures radioactive decay, accelerator mass spectrometry counts 14C atoms relative to stable carbon isotopes. That is why AMS works with much lower radioactivity and smaller sample volumes.
For clinical pharmacology teams, the benefit is both analytical and practical. Lower radioactivity allows generation of 14C data earlier in development, while still answering questions about absorption, metabolism, excretion, mass balance or absolute bioavailability.
Why consider human ADME and mass balance earlier in development?
Human radiolabeled mass balance studies are generally conducted in late-stage development, once more clinical, nonclinical and CMC information is available. That timing leaves routes of excretion, human metabolites and metabolite abundance unresolved until the program is already advanced.
Wouter’s central point is that microtracer studies can move those data earlier. If you understand human excretion routes and metabolic pathways in Phase 1 or Phase 2a, you can plan drug-drug interaction studies, hepatic and renal impairment studies, PBPK modelling and metabolite safety delivering a stronger human data foundation.
Timing matters most when the result could change later decisions. An unexpected human metabolite found late can trigger additional nonclinical or analytical work. Earlier metabolite profiling gives the team time to respond before the issue reaches the critical path.
“The major point is that microtracer approach enables a shorter path to market entry.”
-Wouter Vaes, Chief Science Officer at Peregrion
That quote captures the business case. The value of an AMS microtracer study is not the unit cost of sample analysis. It is the chance to answer human ADME questions earlier, improve the design of follow-up studies and reduce the risk of late program delays.
Can you add a microtracer study to an existing Phase 1 or Phase 2 trial?
In many cases, a microtracer study can be added as a dedicated arm or cohort rather than a separate study. Wouter calls this piggybacking: the team adds the 14C-labeled microtracer and the required additional sampling to a trial that is already planned.
The operational work still matters. Sponsors need appropriate 14C-labelled material, formulation planning, sample schedules, logistics, documentation and analytical execution. The difference is that the lower activity makes the clinical and radiation-handling burden more manageable than a conventional high-activity radiolabeled design.
For Sponsors, the practical question is whether a microtracer arm answers the most important development question: human mass balance, metabolite profiling, fraction absorbed, routes of excretion or absolute bioavailability.
How does AMS compare with liquid scintillation counting?
Liquid scintillation counting is a decay-counting technique. It remains useful for many conventional radiolabeled studies but requires higher radioactive exposure and larger sample volumes than AMS. AMS measures the 14C isotopes directly, which is why it supports low-radioactivity microtracerdesigns.
| Dimension | Traditional high-dose 14C / LSC approach | AMS microtracer approach |
| Analyticalprinciple | Measures radioactive decay. | Measures 14C / 12C ratio. |
| Radiolabeleddose | High 14C activity is generally needed to generate a measurable signal. | Much lower 14C activity can be used. In the podcast, Wouter gives anexample where the radioactivity is around 100-fold lower. |
| Sensitivity | Adequate for many conventional mass balance studies but limited for low exposure and metabolite profiling. | Wouter describes at least 250x higher sensitivity for blood, plasma and urine, and up to 10,000x higher sensitivity for metabolite profiling. |
| Sample volume | Larger volumes are typically needed. | Very small volumes are sufficient. Peregrion cites microliter-scale sample volumes for total 14C and PK/metabolite profiling work. |
| Study timing | Can only be conducted later, once a larger development package is available; it is not considered ethical to do it early-stage (Ethics ICRP 62). | Can be considered in Phase 1 or Phase 2a, depending on program, protocol, ethics and regulatory strategy. |
| Data use | Mass balance and excretion data may arrive after key development decisions are already underway. | Earlier human ADME data will guideDDI, impairment, PBPK, formulation and metabolite safety decisions. |
How do AMS and high-resolution MS work together in metabolite profiling?
AMS quantifies where 14C-labelled drug-related material is present. Structural identification comes from chromatographic separation combined with high-resolution mass spectrometry.
In the workflow Wouter describes, UPLC separates parent drug and metabolites, AMS measures fractions to determine where the radiolabeled material elutes, and high-resolution MS/MS works at the same retention time to support structural identification. AMS provides the total 14C quantification signal, while hrMS/MS provides the structural identification.
How can AMS microtracer studies accelerate oncology drug development?
Oncology is a particularly relevant setting because early clinical development often takes place in patients, not healthy participants. Many oncology compounds are not suitable for healthy-participant studies, and Phase 1/2a programs are commonly run in academic or specialized hospitals.
This creates a mismatch with the traditional late-stage human ADME model. A microtracer arm in an early oncology trial can generate human ADME and metabolite data from the patient population already being studied.
The benefit is not only logistical. Oncology patients are often co-medicated, and real-world use will frequently involve co-medication as well. Early data on metabolism and routes of excretion help teams anticipate DDI questions and decide which follow-up studies are genuinely needed.
Wouter also refers to a published Merck example in which a microtracer-based mass balance, pharmacokinetic and excretion assessment of [14C]berzosertib was conducted in patients with advanced solid tumors. That Phase 1 study shows how the approach applies in an oncology patient setting rather than only in healthy participants.
What does this mean for CMC and Qualified Material?
Radiolabeled material is not just an analytical detail. It affects CMC planning, manufacturing timelines, quality release and internal approval. In a conventional high-radioactivity design, the radiolabeled material represents a large fraction of the administered dose, which requires GMP manufacture.
In a microtracer design, the amount of radiolabeled material sits far below impurity qualification thresholds. That creates a basis for a risk-based discussion around Qualified Material, provided the material is well characterized, appropriately controlled and accepted by the relevant internal and external stakeholders.
This is not a shortcut around quality. It is a planning point. Sponsors need early alignment between clinical pharmacology, DMPK, CMC, QA, QP, ethics and regulatory teams so the 14C-labelled material strategy does not become the bottleneck.
What is the relevance of the 2024 FDA mass balance guidance?
In July 2024, FDA published final guidance on clinical pharmacology considerations for human radiolabelled mass balance studies. The FDA recommends doing these studies early:
“Usually, sponsors have conducted human in vivo metabolism studies relatively later in drug development, but we strongly recommend that sponsors conduct in vivo metabolic evaluation in humans as early as feasible.”
For teams considering AMS microtracer studies, the practical message is that these studies are not only a compliance exercise. Their value depends on timing, study design and how the results inform the broader development program.
The podcast connects the regulatory context to the practical opportunity: since lower 14C activity allows early execution of the study, mass balance and related clinical pharmacology data can contribute to development decisions while there is still time to act on them.
FAQ: AMS microtracer studies in drug development
How much lower is the radiation dose in a microtracer study?
It is program-specific. A microtracer design keeps 14C activity low enough to ease the clinical and radiation-handling requirements while still producing a measurable AMS signal. Generally < 1 uCi The exact reduction depends on the compound, the question and the protocol.
What is the difference between mass balance and absolute bioavailability?
A mass balance study shows the excretion routes of drug-related material after dosing and how much is recovered. An absolute bioavailability study compares systemic exposure after extravascular and intravenous dosing to estimate the fraction of the drug that reaches systemic circulation.
Can AMS identify metabolites directly?
No. AMS quantifies 14C-labelled drug-related material. Metabolite identification is done via chromatographic separation and high-resolution MS/MS. This can be done in one go in the Peregrion facility using LC-MS/MS-(offline)AMS
Does the 14C-labelled material need to be manufactured under GMP?
It requires a program-specific assessment. Qualified Material may be acceptable in some microtracer designs, but it needs alignment with PI, CMC, QA, QP, ethics and regulatory stakeholders.
Can microtracer studies be used in oncology patients?
Yes. The podcast highlights oncology as a strong use case, and the published [14C]berzosertib Phase 1 study in patients with advanced solid tumours is a real-world example.
The central message: plan human ADME earlier
The main takeaway from Wouter’s podcast appearance is that human ADME planning should start early enough for the data to influence development programs.
Mass balance, metabolite profile, route-of-excretion or absolute bioavailability data could impact your DDI strategy, impairment study planning, formulation work or nonclinical follow-up. Waiting until late development therefore adds risk. AMS microtracer studies give clinical pharmacology teams a way to answer these questions earlier.
Listen to the full episode or discuss your study design
Listen to Wouter Vaes on the Clinical Pharmacology Podcast or contact the Peregrion team to discuss how an AMS microtracer study could fit into your development program: info@peregrion.com
About Wouter Vaes
Wouter Vaes, PhD, is Chief Science Officer and co-founder of Peregrion BV. He founded the earlier TNO AMS laboratories and has more than 25 years of experience leading GxP, ISO 17025 and ISO 9001 accredited laboratories. His work focuses on applying AMS and microtracer technologies to generate early human ADME, mass balance, metabolite profiling and absolute bioavailability data for drug development programs.
Further reading and sources
