Delivering Human ADME Studies
The study of drug absorption, distribution, metabolism, and excretion, also known as ADME are used by researchers to analyse and investigate how the body processes a drug compound. In studies like these, experts are seeking answers to some very important questions such as:
- Where does the drug go in the human body?
- What happens to the drug inside the body?
The answers to these questions help scientists progress the drug candidate further into development towards regulatory submission. Quotient Sciences has been delivering radiolabelled clinical studies for the pharmaceutical industry at our Nottingham, UK facility since 2006. We have expertise in conducting conventional human ADME studies, intravenous microtracer and microdose studies, and integrated study designs. We have been at the forefront of driving best practices to simplify study delivery while maximizing data output to ensure clients can learn as much as possible about their candidate drug from a study that should only need to be performed once in the development program for any new chemical entity.
For a relatively simple study design, such as a single radiolabelled dose and subsequent sample collection, the human ADME study can be a complex program of work to deliver. We have always focused on the need to simplify the process for our clients. Our Synthesis-to-Clinic® approach brings together the key building blocks for successful study delivery in a coherent fashion that the client can understand and work into their overall development timeline.
At the outset, the coordination of the synthesis of 14C drug substance and the justification of the proposed radiolabelled dose from animal dosimetry data are critical deliverables. Dosing on the human ADME study can’t be scheduled without an understanding of when the 14C drug substance will be delivered, and that can’t be determined until the radiolabelled dose is confirmed so the target amount of radioactivity in relation to the mass of drug can be fixed.
Gaining the necessary approvals for a radiolabelled study are similar to any other clinical pharmacology study. One difference is the addition of the submission to and approval from an Administration of Radioactive Substances Advisory Committee (ARSAC). As such, the experience of our regulatory department, which routinely progresses clinical trial applications through the MHRA and ethics committees, is pivotal in ensuring that we gain approval for these studies in an optimal timeframe.
Ahead of submission, our team develop a bespoke drug product formulation for the study. For an ADME study, this is usually a simple solution, suspension, or drug in capsule for an oral drug product - something that is not very complex. However, there are limitations on the manipulation of the drug substance due to the radiolabelled content and restrictions on the use of excipients that may interfere with the subsequent sample analysis for metabolite characterization. It is extremely helpful to be able to rely on the experienced formulation capabilities built up over years to ensure a fit-for-purpose drug product can be developed, along with the necessary data needed for the drug product section of the Investigational Medicinal Product Dossier (IMPD).
Conducting an ADME study in the clinic is straightforward and involves the administration of the drug product followed by extensive sample collection from volunteers. There are strict limits to the number of radiolabelled studies that a volunteer can take part in and we adhere to those guidelines. Typically, a human ADME study will have a main residency period of a target duration written into the protocol. There will also be set discharge criteria and volunteers will complete the study when these are met. During the residency period, we will collect all excreta as well as an agreed schedule of blood samples for analysis. The discharge criteria are usually linked to the mass balance recovery and as such, the excreta samples collected from volunteers are analyzed daily so that we are able to construct a cumulative mass balance as the residency period continues. When the criteria are met, volunteers can be discharged, however, there are always contingencies for extra collections if the criteria are not quite achieved in the target time period.
Our metabolism laboratory conducts the analysis of excreta for mass balance and reports results daily, allowing us to generate the mass balance data that leads eventually to subject discharge. The radioactivity determined in the plasma and excreta samples then enables the pooling strategy for metabolite profiling which will identify any metabolites that might need to be fully characterized. The mass balance data will be reported routinely within the clinical study report while the metabolite characterization will be reported separately and appended to the clinical study report when it becomes available.
We are often asked to incorporate an intravenous microtracer period into the study design of the human ADME study and these integrated IVMT/ADME studies now represent the majority of the radiolabelled studies we perform. At a basic level, these designs enable an assessment of absolute oral bioavailability of the clinical stage drug product together with the mass balance and metabolite characterization assessments, however by extending the sample collections and the scope of sample analysis and by comparing data across the IVMT period and ADME period we can investigate in greater detail the overall disposition of the drug product. The extent of the additional scope of work will always be driven by the requirements of the client development team and their drug product.
The strength of our operational teams is a critical factor in the successful delivery of the studies we perform. The ability of our scientific and medical teams to perform detailed interpretations of the data generated from the studies performed helps in ensuring we can maximize our clients' understanding of the routes and rates of elimination of their drug in the human system.
Contact us today to learn more about our 14C human ADME capabilities and talk about your next program.