The pharmacokinetic properties of a new chemical entity (NCE) or an investigational medicinal product (IMP) must be elucidated during clinical drug development. This includes the analysis of their absorption, distribution, metabolism, and excretion (ADME) and is achieved by conducting ADME studies, also known as human mass balance studies. Furthermore, determining the pharmacokinetic properties of an NCE or an IMP may have implications for decisions related to their formulation, dose range, administration route, and frequency of administration.

In this article, we’ll review the objectives, and the design and performance of absorption, distribution, metabolism, and excretion studies.

The Objectives of ADME Studies

The main goals of an Absorption Distribution Metabolism and Excretion study are two-fold:

1. 1. To identify and quantify circulating drug metabolites in relation to the parent drug and/or the total drug‐related exposure – ADME studies aim to provide insight into the pharmacological activity of metabolites and their potential involvement in drug-drug interactions. They also determine which metabolites should be characterized and subjected to a nonclinical safety assessment. Generally, it is accepted that metabolites accounting for over 10% of the total drug-related exposure in plasma should be characterized structurally.
   2. To identify the relevant metabolic and excretion pathways – ADME studies also aim to acquire data on the pathways involved in the metabolism and excretion of NCEs. These data can help decide whether further studies are required to assess the effects of renal and hepatic function and impairment, as well as the role of drug-drug interactions. In addition, they may provide insight into the expected extent of interpersonal variations in certain populations, such as elderly patients and children.

The Design and Performance of ADME Studies

It is strongly recommended to carry out ADME studies for all NCEs unless specific concerns prevent them (such as safety considerations). Factors that should be accounted for in the design and conduct of ADME studies include:

Study design: Human radiolabel studies have been established as the standard type of investigation to elucidate the ADME properties of NCEs in humans. They can be conducted as open-label, non-randomized investigations. Typically, the administration of a single dose is sufficient, whereas multiple doses are required in rarer cases. Generally, the NCE doses used in ADME studies should be within the range examined for efficacy in clinical trials.

Study participants: Most commonly, healthy adults are enrolled in ADME studies unless there are safety concerns related to the administration of the drug in healthy individuals (e.g., toxicity concerns in oncology studies). The final number of recruited participants depends on the drug characteristics and study objectives. However, generally, it is recommended to recruit at least six healthy adults for an Absorption Distribution Metabolism and Excretion study.

Drug administration: The traditional approach for conducting ADME studies includes dosing 14C-radiolabeled material and collecting blood/plasma/serum and excreta (such as urine and feces). Typically, a single, clinically relevant dose of the 14C-radiolabeled drug is used, with the radiolabel placed in a nonlabile position. The choice of a radioactive dose should comply with the relevant guidelines and may be facilitated by the findings of animal dosimetry studies.

Administration route: Unless there are specific concerns, the employed route of administration in ADME studies should be consistent with the intended final route of administration. However, for orally administered NCEs, assessing their absolute bioavailability and including an intravenous arm may help to fully elucidate the pathways implicated in drug elimination.

Sample collection: Blood/plasma/serum and excreta are typically collected for 7–10 days. Sample collection is usually terminated when approximately 90% of the administered radioactivity is recovered, or less than 1% of radioactivity is collected on two consecutive days. This approach aims to optimize the total recovery of radioactivity in the collected samples and to enable the identification of all relevant metabolites, even if they appear late or are persistent.

Sample storage: The storage conditions should ensure the stability of the samples until subsequent analyses. If the analyzed NCEs or their metabolites are unstable or metabolized in blood, adding stabilizers to the collection tubes is required.

Sample analysis: The samples can be analyzed for the parent drug candidate and its metabolites using multiple bioanalytical methods. Several factors may affect the choice of a bioanalytical method, including the study objective, the limit of detection of each method, and the levels of all moieties of interest. Relevant methods for the bioanalysis may include scintillation counting, high-performance liquid chromatography (HPLC) with radio-detection and accelerator mass spectrometry (AMS) (especially for microtracer studies), and liquid chromatography with tandem mass spectrometry (LC/MS/MS).

Study report: The prepared study report should include data on the plasma concentration versus time profiles and pharmacokinetic parameters for the total radioactivity and non-radiolabeled moieties; the percentage of the recovered radioactive dose in urine, feces, and total excreta versus time profiles; and quantitative data on the radioactivity associated with the parent drug candidate and each identified metabolite in the collected biomatrices.

The Timing of ADME Studies and Clinical Drug Development

The results of ADME and related studies are generally required before initiating Phase 3 trials and should be included in the regulatory submission for marketing authorization. Moreover, there has been a shift toward conducting ADME studies earlier during clinical drug development and before the demonstration of efficacy. The early initiation of ADME studies allows sufficient time to perform the structural characterization and safety assessment of relevant metabolites. Early initiation also enables the faster delivery of a complete package for a marketing authorization application. The timing of ADME studies may also be affected by the drug indication.

Alternatives When an ADME Study Is Not Possible

If an Absorption Distribution Metabolism and Excretion study is not possible, such as for safety reasons, in vitro assessments and animal radiolabeled mass balance studies may be employed. However, it may be challenging to extrapolate animal data to humans due to interspecies differences in drug metabolism and excretion.

Why Choose BioPharma Services?

BioPharma Services, Inc. (BioPharma) is an award-winning, full-service clinical research organization (CRO) with expertise in all aspects of the design and performance of clinical trials, including ADME studies. The unique set of strengths that we bring to clinical drug development programs of our clients include:

A team of proficient clinical pharmacologists and pharmacokinetic scientists – Our clinical pharmacologists and pharmacokinetic scientists have successfully supported thousands of clinical trials, including ADME studies. The team is led by BioPharma’s chief scientific officer (CSO), Dr. John Oldenhof, who is a widely recognized expert in the field of clinical pharmacology with over 25-year experience.

A state-of-the-art, in-house bioanalytical laboratory – BioPharma has established a bioanalytical laboratory equipped with a state-of-the-art LC/MS/MS platform that enables us to perform all relevant bioanalyses in-house. We have completely validated over 230 bioanalytical assays to address the diverse needs of our clients’ clinical trial programs.

Modern clinical facilities and expert physicians – BioPharma has established two clinical research centers designed to ascertain participants’ safety while efficiently generating clinical trial data. Our expert physicians ensure the safety and well-being of study volunteers in all clinical trials, including ADME studies.

Access to an extensive database of study volunteers – BioPharma has created a large database with over 18,000 potential study participants, including normal healthy volunteers (NHVs) and special populations.

Experience with various formulations and routes of administration – The pharmacokinetic properties of NCEs can also be influenced by their formulation and route of administration. BioPharma has expertise in working with various drug formulations and routes of administration due to the expertise of our team and network of external collaborators.

Integration of ADME data into the overall clinical trial results – The members of our multidisciplinary team collaborate to efficiently integrate the results of the ADME studies with other clinical trial data to streamline the drug development process.

BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.