Delivering Human ADME Studies in 2020 and Beyond

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 facility in Nottingham in the UK since 2006. Our expertise lies 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 (single radiolabelled dose and subsequent sample collection), the human ADME study can be a complex program of work to deliver.  At Quotient, we have always focused on the need to simplify the Synthesis-to-Clinic® process for our clients – bringing together the key elements or building blocks needed 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 the key 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 that the target specific activity (the amount of radioactivity in relation to the mass of drug) can be fixed.

With the addition of the need to obtain approval for the radioactive dose through a submission to ARSAC (Administration of Radioactive Substances Advisory Committee), gaining the necessary approvals for a radiolabelled study are essentially similar to any other clinical pharmacology study.. As such, the experience of Quotient’s regulatory group who routinely progress clinical trial applications through the MHRA and ethics committees is pivotal in ensuring that we gain approval for these studies in an optimal timeframe. In the UK, the MHRA have a timeline of 30 days for review of phase I submissions and we routinely find that we obtain approvals in a shorter time period than this.

As part of that process, and ahead of submission, our pharmaceutical development team will 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 so 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 characterisation. That being said, it is extremely helpful to be able to rely on the experienced formulation capabilities built up over years and the experience of over 150 ADME studies to ensure that a fit for purpose drug product can be developed together with all the necessary data needed for the drug product section of the IMPD (Investigational Medicinal Product Dossier).

The conduct of an ADME study in the clinic is straightforward.  Administration of the drug product followed by the need to comply with extensive sample collection is aided in many cases by a volunteer panel experienced in the constraints an ADME study can require.  There are strict limits to the number of radiolabelled studies human subjects can take part in and as with every other clinic, Quotient adheres to the guidelines with regard to subject participation.  That said, our volunteers often return, as allowed, particularly to participate in ADME studies and this helps their understanding for the need of complete compliance with sample collection requirements.

Typically, a human ADME study will have a main residency period of a target duration written into the protocol but there will also be a set discharge criteria, and subjects will complete the study when these are met.  During that 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 analysed daily so that we are able to construct a cumulative mass balance as the residency period continues.  When the criteria are met, the subjects can be discharged, however, there are always contingencies for extra collections [I1] if the criteria are not quite achieved in the targeted time period.

Our metabolism laboratory conduct the analysis of excreta for mass balance and report results on a daily basis 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 characterised. The mass balance data will be reported routinely within the clinical study report while the metabolite characterisation 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 the most basic level these designs enable an assessment of absolute oral bioavailability of the clinical stage drug product together with the mass balance and metabolite characterisation 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 or 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 interpretation of the data generated from the studies performed helps in ensuring we can maximise our clients understanding of the routes and rates of elimination of their drug in the human system.

Click here for more information on Quotient’s 14C ADME capabilities.