Integrating Duodenal Sampling in a Human Mass Balance Study to Quantify the Elimination Pathways of JNJ-53718678, a Respiratory Syncytial Virus Fusion Protein Inhibitor

Remmerie, Bart; Boer, Maarten van den; Looy, Thomas Van; Wynant, Inneke; Rusch, Sarah; Huntjens, Dymphy; Meulder, Marc De; Stevens, Marita

doi:10.1007/s12325-019-01162-7

Cited by 3 publications

(4 citation statements)

References 19 publications

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“…In vitro studies using radiolabeled drug can sometimes be considered useful, for example, using hepatocytes 17 . There are, however, alternative views that, in contemporaneous drug development, such concerns are generally mitigated, due to the technical and associated advances made with cold (non‐radiolabel) approaches, 18,19 including the relative ease of collecting human bile with non‐ or minimally invasively devices, such as the Entero‐test 20 or other duodenal fluid sampling approaches 21,22 . Indeed, assessment of metabolites of human relevance from the analysis of samples from the first time in human (FTIH) and toxicology studies is now standard early in development (see Figure ).…”

Section: Strategy Design and Implementationmentioning

confidence: 99%

“…17 There are, however, alternative views that, in contemporaneous drug development, such concerns are generally mitigated, due to the technical and associated advances made with cold (non-radiolabel) approaches, 18,19 including the relative ease of collecting human bile with non-or minimally invasively devices, such as the Entero-test 20 or other duodenal fluid sampling approaches. 21,22 Indeed, assessment of metabolites of human relevance from the analysis of samples from the first time in human (FTIH) and toxicology studies is now standard early in development (see Figure 1). In some instances, metabolites identified in early work are synthesized so that they are available (e.g., as chromatographic standards) to aid peak resolution assessments.…”

Section: Strategy Design and Implementationmentioning

confidence: 99%

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Considerations for Human ADME Strategy and Design Paradigm Shift(s) – An Industry White Paper

Young

Spracklin

James

et al. 2022

Clin Pharma and Therapeutics

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The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug-related material in humans through the use of 14 C-labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re-think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company. The paper also provides a framework for continuing the discussion in the application of further shifts in the paradigm.

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Section: Strategy Design and Implementationmentioning

confidence: 99%

Section: Strategy Design and Implementationmentioning

confidence: 99%

Considerations for Human ADME Strategy and Design Paradigm Shift(s) – An Industry White Paper

Young

Spracklin

James

et al. 2022

Clin Pharma and Therapeutics

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“…Although the stability of the radiolabel within the drug moiety is often confirmed by collecting and analyzing expired CO 2 during preclinical absorption, distribution, metabolism, and excretion (ADME) studies, several study designs include sparse collection of expired air to preclude expiration of unique volatile human metabolites. Human bile may also be collected and analyzed with minimally invasive devices, such as the EnteroTracker or other duodenal fluid sampling approaches 10–12 …”

Section: Study Aims and End Pointsmentioning

confidence: 99%

“…Human bile may also be collected and analyzed with minimally invasive devices, such as the EnteroTracker or other duodenal fluid sampling approaches. [10][11][12] Radiolabeled studies are not statistically powered so the panel size typically requested is small and has ranged from 4 to 12 over the last 27 years for which we have data. With the new FDA guidance issued (May 2022) a recommendation was made for at least six evaluable subjects and as a result most studies now are planned with a recruitment panel of eight subjects, allowing for any unexpected subject dropouts, with at least six subjects fulfilling the study requirements.…”

Section: Study Aims and End Pointsmentioning

confidence: 99%

The Changing Landscape for Human Absorption, Metabolism, and Excretion: Practical Experiences From a Data Analysis of 500 Studies

Kendrick,

Oelke,

Laing

et al. 2023

Clin Pharma and Therapeutics

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Coincidental with the intensified regulatory and industry focus on the design and conduct of human absorption, metabolism, and excretion (hAME) studies in the past 12 months, we have recently completed our 500th cohort involving radiolabeled test item administration to humans. Here, we build upon a recent industry white paper in this journal1 and share some of our own experiences as a Contract Research Organization based upon collaborations with numerous pharma companies and their differing approaches to design and timing, to add further context to the discussion regarding hAME studies and the pivotal role that drug metabolism and pharmacokinetics plays. In this article, we explore how both changing relationships within the industry and shifting regulatory guidelines are impacting strategies, and compare EU and US pre‐study approval requirements, before evaluating the trends from over 500 studies conducted at our global facilities conducted over more than 30 years. We conclude with a review of how improved technical capabilities and strategies are influencing the design and conduct of hAME studies, before speculating on some of the driving factors which may shape the direction they take in the future.

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Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

Wong

2023

Overcoming Obstacles in Drug Discovery and Development

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Integrating Duodenal Sampling in a Human Mass Balance Study to Quantify the Elimination Pathways of JNJ-53718678, a Respiratory Syncytial Virus Fusion Protein Inhibitor

Cited by 3 publications

References 19 publications

Considerations for Human ADME Strategy and Design Paradigm Shift(s) – An Industry White Paper

Considerations for Human ADME Strategy and Design Paradigm Shift(s) – An Industry White Paper

The Changing Landscape for Human Absorption, Metabolism, and Excretion: Practical Experiences From a Data Analysis of 500 Studies

Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

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