Maximizing your clinical datapackage with absolute bioavailability
Absolute bioavailability studies determine the fraction of your drug that reaches systemic circulation unchanged. Microtracer IV formulations can be administered in parallel to oral therapies, making the best use of participants’ presence in the clinic, time and money.
Add your absolute bioavailability studies onto existing clinical trials
Studies into absolute bioavailability measure the exact fraction of a drug that reaches the systemic circulation unchanged. The information helps to quantify pre-systemic losses, for example, via first-pass effects.
Absolute bioavailability studies via the IV microtracer approach can be added to cold oral treatment in existing Phase 1 trials. This is enabled by the microdose of drug product that is used for IV microtracer studies. The microdose is considered as an impurity on top of the cold dose. This has two important advantages: 1. nonclinical IV tox studies can be waived; 2. oral and IV pharmacokinetics are measured in the same subjects, minimizing inter-subject variability and improving data quality. Piggybacking microtracer IV studies onto existing trials strongly enriches your clinical data package without the need for additional participants and extended clinical stays.
Absolute bioavailability studies provide critical pharmacokinetic parameters including: absolute bioavailability (F), fraction absorbed (Fa), systemic clearance (CL), volume of distribution (Vd). The optimal study design for your specific case will be developed jointly with our scientists. For instance, in some cases determination of fraction absorbed may be the preferred route to achieve your goals. We take pride in effective study designs and in transparent communication and recommendations.
When absolute bioavailability studies are essential for your drug development program
You need to confirm the therapeutic window
You need guidance on the dosing regime to understand if the systemic exposure of the drug falls within the therapeutic window. If a large fraction of the drug is found unchanged in feces, bioavailability data supports understanding of the role of first-pass metabolism.
You are optimising a novel formulation
You are working on innovative formulations with limited information on the uptake and clearance routes. Early-stage studies provide ample time to redesign and optimize the formulation.
Your compound should stay out of the bloodstream
For instance, your compound is designed to be active in the gastrointestinal tract. Confirmation of low bioavailability endorses the intended use, particularly if the fraction absorbed is also low.
Practical study information for absolute bioavailability
| Parameter | Peregrion AMS Approach | Client Benefit |
|---|---|---|
| Typical cohort size | 6-8 participants that receive cold oral administration | no additional cohort needed, as the microdose IV formulation can be added on top of cold administration |
| Study design | recommendations on clinical and bioanalytical study design, e.g. one-arm vs two-arm, dosing, bioanalytical methods | optimal study design based on expertise and experience |
| Sample matrix: absolute bioavailability | plasma | direct measurement, no sample preparation needed |
| Sample matrix: fraction absorbed* | urine | easy add-on to absolute bioavailability studies |
| Solubility of radiolabeled IV formulations | a microdose of the drug is sufficient | in case the solubility of your hydrophobic small molecule is poor at regular dose levels, the preparation of the IV formulation for conventional studies is problematic. At a microdose level, solubility is rarely an issue |
| Prior toxicology studies | the microdose of the drug is considered an impurity | Preclinical IV toxicology studies can be waived |
| Radiation dose | ≤ 1 µCi; 100-1,000 lower than conventional studies | microtracer studies are approved as early as Phase 0, as the radiolabeled product falls in ICRP Class I |
| Method qualification | based on EBF recommendation and, where applicable, the ICH M10 guideline | absolute bioavailability studies are compliant with regulatory requirements |
*The relevance of the fraction absorbed becomes most prominent if the absolute bioavailability is low. As a low absolute bioavailability with a low fraction absorbed indicates that absorption is limiting the oral bioavailability which may justify extensive formulation optimization. In contrast, a low absolute bioavailability with a high fraction absorbed indicates first pass metabolism, which does not justify further formulation development
Intravenous microtracer absolute bioavailability studies can be added to
cold oral administration
No additional cohorts needed. The IV microdose is given around Tmax of the cold oral administration. The same individuals can receive cold oral and microtracer IV administration at the same time, which enables inclusion of the absolute bioavailability study in existing trials wih only a modest incremental cost. This enhances the flexibility and ease of doing absolute bioavailability studies. It provides tremendous enrichment of your human data package whilst being an efficient add-on to ongoing studies. Because these insights become available early in Phase 1, absolute bioavailability studies have a direct impact on key development decisions before Phase 2.
Large enrichment of your human data package with minimal effort
Guided by Scientific Experts
Alana Pereira
Alana is a chemist with a PhD in Organic and Analytical Chemistry, specializing in Metabolomics and Chemical Ecology. She has over three years of experience as a scientist in AMS microtracer research, with expertise in mass balance, absolute bioavailability, and metabolite profiling studies.
Sabrina Hanswijk
Sabrina has a background in biomedical sciences and holds a PhD in neuroscience. She has 5 years experience as a scientist in AMS with her main focus on mass balance and absolute bioavailability studies.
Lotte van Andel
Lotte brings a bioanalysis background and a PhD (Netherlands Cancer Institute/NKI) in conventional high-dose human ADME studies. With six years of total industry experience, she has spent three years working as a scientist and three years as a project manager. She currently also serves as Team Lead of the Research Technician group.
Related Services
Mass Balance
Total Radioactivity in excreta, whole blood and plasma (% recovered), urine versus feces excretion (%), PK profile in plasma and whole blood, AUC, Cmax, t½. Participants can be discharged from the clinic when 90% of radioactivity has been recovered in the samples.
Metabolite Profiling
Comprehensive snapshot of metabolites in biological samples. Relative abundance (%) of parent drug and metabolites using UPLC in combination with AMS technology.
Metabolite Identification
Structure of unknown metabolites in biological samples. Metabolites are identified using UPLC in combination with hrMS/MS technology.
Feces Homogenization and Excretion Balance Reporting
Feces homogenization is required for effective analysis of parent drugs and metabolites. Peregrion has a dedicated microtracer-only feces homogenization facility. Using the homogenization data, Peregrion can perform rapid reporting of the excretion in urine and feces (% of dose). For this, Peregrion requires the transfer of urine weights in Excel format (as part of the shipment documentation) and the actual dose administered to the participants (single data transfer).
Resources & Publications
New publication on a long-duration microtracer ADME study of osivelotor
A newly published Phase 1 study shows how microtracer dosing and AMS enabled the characterisation of osivelotor’s mass balance and…
New publication on xevinapant absolute bioavailability and human ADME
A Phase 1 study on the absolute bioavailability, pharmacokinetics, metabolism and excretion of xevinapant has been published open access in…
FAQs
What is the difference between mass balance and absolute bioavailability?
A mass balance study shows the excretion routes of where drug-related material goes after dosing and how much is recovered. An absolute bioavailability study compares systemic exposure after extravascular and intravenous dosing to estimate the fraction that reaches systemic circulation. Information on absolute bioavailability can help interpret mass balance data and understand the overall drug elimination pathways. For instance, if a large fraction of the drug is found unchanged in feces, bioavailability data supports understanding of the role of biliary and/or gut wall secretion to drug elimination.
Is 6 participants enough for regulators?
Indeed. 6 participants is generally sufficient for regulators. Some companies have submitted NDAs using 4 participants. The minimum depends on the compound and the disease indication and is often based on company policies.
What are the combined advantages of microtracer studies in clinical development?
Overall, the microtracer-based mass balance, metabolite profiling and absolute bioavailability studies in early clinical developments give an enormous enrichment of the data package available at early-stage without the need for separate studies to determine human ADME data. The data richness allows better study designs for follow up clinical studies, it allows earlier assessment and risk mitigation strategies for unexpected human unique metabolites, and it eliminates the need to conduct radioactive animal mass balance/metabolite profiling studies, where many animals, and much time and money are being spent on non-relevant animal metabolites.
Is human ADME data that is generated with microtracer studies acceptable for regulatory submissions?
The answer is ‘Yes’. We deliver data to our clients to support their regulatory submissions with regulatory-required or requested data such as human metabolism, routes of excretion, absolute bioavailability, and fraction absorbed. The FDA guideline on Safety Testing of Drug Metabolites Guidance for Industry (CDER) March 2020 Pharmacology/Toxicology recommends performing human in vivo metabolic evaluation as early as possible. The level of radioactivity in a microtracer study is only 0.1-1µCi. Conventional studies generally apply 100µCi. Due to the 100-fold lower radioactivity levels, ethical committees approve the use of 14C microtracers in early-stage clinical development.
What is a microdosing study in the context of a microtracer study?
A microdosing study includes a very low dose of the drug product (e.g. 100 µg) with a 14C microtracer. Due to the low dose (considered as an impurity) there is no toxicological concern and only a limited pre-clinical package is required to conduct such a study. This comes with the advantage that fewer lab animals are needed. Multiple drugs can be administered in the same study in parallel groups to aid in PK based candidate selection. A typical microdosing study consists of approximately 6 volunteers per drug. The microdose can be administered via any route, e.g. oral or intravenous.