Human absorption, distribution, metabolism, and excretion studies: Conventional or microtracer?

Abstract

A human absorption, distribution, metabolism, and excretion (hADME) study is an essential clinical pharmacology study for small-molecule drugs. The study provides insights into circulating drug-related materials and the drug's elimination pathways in humans, which can guide future studies on safety and drug-drug interaction of metabolites as well as organ impairment and drug-drug interaction of the parent drug. The 2 hADME study types, namely conventional and microtracer, are comprehensively compared in this manuscript. A review of literature found that conventional hADME studies were approximately 7 times that of microtracer hADME studies for small molecule and peptide drugs based on publications in 3 peer-reviewed journals from 2010 to 2024. Each study type has advantages and disadvantages. The advantages of conventional hADME studies primarily include the ease, low cost, and flexibility of radiometric sample analysis. In contrast, the advantages of microtracer hADME studies primarily include exemption from prerequisite studies and use of non-good manufacturing practice ¹⁴C-labeled materials. The disadvantages of each study type are essentially the advantages of the other. The manuscript also discusses scenarios where a microtracer hADME study may be preferable. Finally, recommendations are provided on selecting the appropriate hADME study type for an investigational drug. SIGNIFICANCE STATEMENT: The manuscript discusses 2 primary human absorption, distribution, metabolism, and excretion study types: conventional and microtracer. It covers published literature studies, the pros and cons of each type, scenarios for conducting microtracer studies, and a recommended decision tree for selecting the appropriate human absorption, distribution, metabolism, and excretion study type.