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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

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Abstract

Introduction

The study objective was to characterize the excretion and metabolic profile of the respiratory syncytial virus fusion protein inhibitor, JNJ-53718678. Prior animal and in vitro studies suggested three main elimination pathways: N-glucuronidation to M8; CYP(3A4) metabolism leading to circulating metabolites M5, M12, M19 and M37; and JNJ-53718678 biliary excretion. To gain insight into the relative contribution of JNJ-53718678 and M8 biliary excretion, duodenal fluid sampling was incorporated into this mass balance study.

Methods

A single oral dose of 500 mg 14C-JNJ-53718678 was administered to six healthy male subjects. Four hours after study drug intake, gallbladder contraction was stimulated and duodenal fluid samples were collected. JNJ-53718678, its key circulating metabolites and total radioactivity (TR) were quantified in plasma, feces, urine and duodenal fluid. Safety was monitored throughout.

Results

JNJ-53718678 and M12 represented 47.4% and 17.8%, respectively, of TR area under the curve (AUC)∞ in plasma. M37 (9.6%), M19 (5.2%), M5 (4.3%) and M8 (1.4%) were minor metabolites; 70.6% of TR was recovered in feces and 19.9% in urine. Duodenal fluid concentrations (% of TR) were highest for JNJ-53718678 (11.6%) followed by M8 (10.4%), M5 (5.9%) and M12 (1.1%). In feces, 10–16% of TR was JNJ-53718678, 5–8% M5, < 1% M12 and < 1% M8. N-glucuronidation to M8 and direct biliary excretion of JNJ-53718678 represented 7% and 8% of drug clearance, respectively. JNJ-53718678 was safe and well tolerated.

Conclusions

JNJ-53718678 is primarily eliminated through CYP3A4-mediated metabolism. By integrating duodenal sampling, N-glucuronidation was confirmed as another metabolic pathway despite the low amount of M8 excreted in urine and feces.

Trial Registration

Eudract no. 2016-002664-14.

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Acknowledgements

The authors thank the study participants for their involvement in the study.

Funding

This study and the Rapid Service Fees were funded by Janssen Sciences Ireland UC. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Medical Writing Assistance

Medical writing support for the preparation of the article was provided by Dr. Claire Kilmartin of Trilogy Writing & Consulting GmbH. This support was funded by Janssen Sciences Ireland UC.

Authorship

All named authors meet the International Committee of Medial Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Bart Remmerie is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Maarten van den Boer is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Thomas Van Looy is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Inneke Wynant is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Sarah Rusch is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Dymphy Huntjens is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Marc De Meulder is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock. Marita Stevens is an employee of Janssen Pharmaceutica and may own Johnson & Johnson stock.

Compliance with Ethics Guidelines

The study was approved by the Independent Ethics Committee (Medisch Ethische Toetsingscommissie) of the Foundation “Evaluation of Ethics in Biomedical Research” (“Stichting Beoordeling Ethiek Biomedisch Onderzoek”), Assen, The Netherlands (JJP264EC-162641). All procedures performed involving human participants were in accordance with the ethical standards of the independent ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Data Availability

The data sharing policy of the Sponsor is available at: https://www.janssen.com/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at: http://yoda.yale.edu.

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Authors and Affiliations

  1. Global Clinical Pharmacology, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Bart Remmerie & Dymphy Huntjens

  2. Clinical Pharmacology Unit, Janssen Research & Development, Lange Bremstraat 70, 2170, Merksem, Belgium

    Maarten van den Boer & Thomas Van Looy

  3. Drug Metabolism and Pharmacokinetics, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Inneke Wynant & Marc De Meulder

  4. Statistical Decision and Sciences, Janssen Biostatistics Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Sarah Rusch

  5. Global Clinical Development Infectious Diseases, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Marita Stevens

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  1. Bart Remmerie
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Correspondence to Bart Remmerie.

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Remmerie, B., van den Boer, M., Van Looy, T. et al. Integrating Duodenal Sampling in a Human Mass Balance Study to Quantify the Elimination Pathways of JNJ-53718678, a Respiratory Syncytial Virus Fusion Protein Inhibitor. Adv Ther 37, 578–591 (2020). https://doi.org/10.1007/s12325-019-01162-7

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