Mini‐Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study

Abstract

The human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study offers a quantitative and comprehensive overall picture of the disposition of a drug, including excretion pattern and metabolite profiles in circulation and excreta. The data gathered from the ADME study are highly informative for developing a cohesive strategy for clinical pharmacology studies. Elements of standard ADME study designs are described. An exciting new development in human ADME studies is the application of accelerator mass spectrometry (AMS) as the detection technique for carbon‐14, in replacement of radioactivity measurements. This technology permits administration of 100‐fold to 1,000‐fold lower amounts of carbon‐14, and thus opens the door to the application of new study designs. A new ADME study design, termed the AMS‐Enabled Human ADME study, is described. In this design, both oral and intravenous administration are assessed in a single clinical study with a two‐period crossover. In addition to all of the standard ADME study end points (e.g., mass balance and quantitative metabolite profiles), the AMS‐Enabled ADME study can provide the fundamental pharmacokinetic parameters of clearance, volume of distribution, absolute oral bioavailability, and even estimates of the fraction of the dose absorbed. Thus, we have entered a new era of human ADME study design that can yield vastly more informative and complete data sets enabling a superior understanding of overall drug disposition.

Physiologically‐Based Pharmacokinetic Models as Enablers of Precision Dosing in Drug Development: Pivotal Role of the Human Mass Balance Study

“…MB studies traditionally use the clinically intended route of administration. While sufficient to address MIST objectives, the value of information from this study can be greatly enhanced for PBPK model development if evaluation of absolute bioavailability is built in 4 . If feces are analyzed for parent drug following intravenous (IV) administration, quantification of biliary plus intestinal secretory clearance will be possible.…”

Absolute Bioavailability, Mass Balance, and Metabolic Profiling Assessment of [14C]‐Belumosudil in Healthy Men: A Phase 1, Open‐Label, 2‐Part Study

“…Mass balance studies are performed to identify and quantify metabolites and determine characteristics of the elimination pathways. [10][11][12] An increasingly popular approach for determining absolute bioavailability is use of a microtracer dose. [13][14][15][16][17] In the phase 1 human mass balance study reported herein, belumosudil PK was characterized in humans after oral doses of 200 mg (unlabeled belumosudil tablet and [ 14 C]-belumosudil capsule) and a radiolabeled intravenous (IV) microtracer.…”

Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data

“…Indeed, for the integrated approach only very low amounts of radiolabeled compound are needed, so that no determination of radiation burden is required, and hence, no quantitative whole-body autoradiography in rodents is to be conducted. In addition, the very low amounts used do not require to be produced according to Good Manufacturing Practice ( Ufer et al, 2017 ; Spracklin et al, 2020 ). However, for such an integrative approach a highly sensitive technique is needed, which is realized by the application of AMS ( Graham and Garner, 2003 ; Lappin et al, 2006 ).…”

“…Additionally, it provides key information on relevant drug interactions or dosing of special patient populations such as renally or hepatically impaired patients. Given the importance of understanding those characteristics, human ADME studies should be conducted during early clinical development ( Spracklin et al, 2020 ). This can be achieved, for example, with a human microtracer component incorporated into a first-in human (FIH) study.…”