Understanding Human ADME
J. Fred Pritchard, Ph.D.
Vice President, Global Drug Development
ADME (Absorption, Distribution, Metabolism, Excretion) is the acronym that has been used for decades to describe studies that address what happens to the drug molecule itself when it is administered to humans and animals used in toxicology assessments. The strategic question for drug developers is how much knowledge about human ADME is needed or valuable at different stages of clinical development. Ultimately, a full understanding of human ADME is an expected element of marketing applications to most major drug regulatory agencies.
For the past 40 years, the primary way that the dispositional fate of a new drug in humans is studied involves administration of a radiolabeled form of the new drug to a small cohort of male healthy participants. The process involves preparation of an appropriately radiolabeled drug (almost always involving 14C) with sufficient specific activity to be measureable using standard scintillation devices. The radioactive dose is usually around 100 microCuries and justified by dosimetry calculated from animal tissue distribution data using the same radiolabeled drug substance. After single dosing, all excreta are collected, volumes/weights measured, and sampled for radioactivity until the levels are low enough that the participants can be safely released from the clinic. Samples of blood, plasma, urine and fecal material are analyzed for parent drug and any known metabolites using validated assays. Finally, the full metabolic profile can be defined by careful chromatographic isolation of radiolabeled metabolites followed by structural identification with mass spectrometry and NMR. The cost and time required to do this work was the key factor for positioning this work later in clinical development, when the decision to commit to regulatory filing had been made. However, recently the pendulum of strategic thought has ADME studies recommended for early Phase II instead of early Phase III for reasons outlined below.
Regulatory and Development Questions
As discussed in more detail elsewhere in this newsletter, both the FDA and EMA have issued guidance aimed at providing a rationale for selection of the animal species to be used to assess chronic toxicology of new drug candidates, based on comparative metabolic profiles. This decision needs to be made during phase II development and is a major factor in justifying human ADME studies earlier in clinical development.
Often, critical questions about a drug’s disposition need to be addressed as part of the Clinical Proof-of-Concept (CPoC) or End of Phase II go/no-go decision gates. Is an active metabolite involved or suspected? Does the drug and or metabolite get to the site of action? What is the extent of first-pass metabolism and how can that be manipulated to achieve better systemic delivery? Is metabolism or membrane transport by the target tissue important? These can provide additional reasons for earlier assessment of human ADME.
Knowledge of Molecular Biology of DMEs (Drug Metabolizing Enzymes)
The last few years has seen a consolidation of knowledge of DMEs and more recently membrane transport and binding proteins that define where and how quickly a drug moves through the body. At a gene and protein level, practical in vitro tests conducted early in drug discovery and preclinical development enable the drug developer to identify the important human enzymes that contribute to a new drug’s metabolism. New drug candidates are selected for metabolic robustness and avoiding clearance that is dependent on human polymorphic DMEs. Marrying this rich knowledge of drug disposition at the molecular level with an early understanding of human ADME in clinical development helps determine what types of drug-drug interactions might or might not be expected. This is an important assessment as patient recruitment will be dependent on what other drugs are allowed to be taken during early clinical studies.
With LC-MS/MS and MS-QTOF instruments evolving with greater sensitivity and analytical flexibility, some drug sponsors have been successful in characterizing a new drug’s metabolic profile, distribution and elimination properties without resorting to a radiolabeled drug. Success with this approach is dependent upon whether the new drug candidate uses relatively few metabolic or transport pathways in its distribution and elimination.
Pressures to know more about human ADME characteristics of NCEs earlier in clinical development stimulated the emergence of other innovative approaches. The use of microtracer doses of radiolabeled drugs (doses below 500 nanoCuries in Nebraska) require no formal dosimetry calculations and hence no animal tissue distribution studies. This can save time and money. However, analysis requires use of accelerator mass spectrometry (AMS) technology that can be provided through a small number of specialty vendors. Moreover, because of the low dose of radioactivity there are no restrictions on movement of participants since the amount of excreted radioactivity is undetectable by scintillation instruments. Participants do not need to be confined to a restricted area of the clinic for many days while radioactive products are washed out of their bodies. Furthermore, this approach is a good solution for studying ADME in patient settings for example, in oncology treatment centers.
Studying ADME earlier in clinical development often demands more flexible ways of preparing radioactive dose formulations. Celerion’s USP<797> accredited pharmacy clean room enables trained pharmacists to prepare doses of radiolabeled drugs from API, for immediate use in the clinic without the cost of GMP manufacturing for a formulation that would likely only be used for one study.
Celerion’s History in Human ADME
For over 20 years, Celerion has been performing human ADME studies at the clinic in Lincoln, Nebraska. Our scientists have the experience, streamlined processes and the relationships with expert vendors to provide a complete solution from radiolabel synthesis to metabolite profiling of radiolabeled studies. Traditional or microtracer approaches can be used to help meet the current challenge of understanding new drug disposition earlier in drug development.