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Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial

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Abstract

Introduction

In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab.

Methods

578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling.

Results

Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data.

Conclusions

BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments.

Trial Registration

This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090.

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Acknowledgments and Disclosures

Dr. Laurie Orloski (independent medical writer) provided writing assistance and Dr. Namit Ghildyal (Janssen Research & Development, LLC.) provided additional editorial support for this manuscript. JdJ, MN MS, AH, MM, and IP are employees of Janssen Research & Development and hold stocks in the company; PC has received research grants from Hoffman-La Roche, Janssen, GlaxoSmithKline, Novartis, and Gilead and fees from AstraZeneca, Hoffmann La Roche, Janssen, Novartis, Astellas, and Mundipharma; GF has received research grants and fees from Janssen and Celgene and fees from Lundbeck; NB has received research grants from Janssen and Pharmacyclics; M-SD has received fees from Gilead, Janssen, and Roche; JL has received fees from Gilead, Janssen, Roche, and Abbvie; SR has received research grants and fees from Janssen, Roche, and Celgene and fees from Pharmacyclics; AG has received research grants and fees from Janssen, Pharmacyclics, Celgene, and Infinity, fees from Takeda and Acerta, and research grants from Genentech; SG has received research grants from Janssen and fees from Onyx and Seattle Genetics; SML, GDN, FD, AA, and OS have no conflicts of interest to disclose. The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff.

Funding

Janssen Research and Development, LLC.

Author information

Author notes

  1. Silvia Maria Lavezzi

    Present address: Quantitative Clinical Development, PAREXEL International, Dublin 8, Ireland

Authors and Affiliations

  1. Department of Electrical, Computer and Biomedical Engineering, Università degli Studi di Pavia, Pavia, Italy

    Silvia Maria Lavezzi & Giuseppe De Nicolao

  2. Janssen R&D, San Diego, California, USA

    Jan de Jong

  3. Janssen R&D, Beerse, Belgium

    Martine Neyens

  4. German CLL Study Group, University Hospital of Cologne, Cologne, Germany

    Paula Cramer

  5. Dokuz Eylul University, Izmir, Turkey

    Fatih Demirkan

  6. Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada

    Graeme Fraser

  7. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, USA

    Nancy Bartlett

  8. Hôpital Haut-Lévêque, Bordeaux, Pessac, France

    Marie-Sarah Dilhuydy

  9. Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain

    Javier Loscertales

  10. Chaim Sheba Medical Center, Tel-Hashomer and Sackler School of Medicine, University of Tel Aviv, Tel Aviv, Israel

    Abraham Avigdor

  11. Derriford Hospital, Plymouth, UK

    Simon Rule

  12. Nizhny Novgorod Regional Clinical Hospital, Nizhny Novgorod, Russia

    Olga Samoilova

  13. John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, USA

    Andre Goy

  14. University of Kansas Medical Center, Kansas City, Kansas, USA

    Siddhartha Ganguly

  15. Raritan, New Jersey, USA

    Mariya Salman & Michelle Mahler

  16. Janssen R&D, High Wycombe, UK

    Angela Howes

  17. Global Clinical Pharmacology, Quantitative Sciences, Janssen-Cilag SpA, Via Michelangelo Buonarroti 23, 20093, Cologno Monzese, MI, Italy

    Italo Poggesi

Authors
  1. Silvia Maria Lavezzi
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  2. Jan de Jong
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  18. Giuseppe De Nicolao
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  19. Italo Poggesi
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Correspondence to Italo Poggesi.

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Lavezzi, S.M., de Jong, J., Neyens, M. et al. Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Pharm Res 36, 93 (2019). https://doi.org/10.1007/s11095-019-2605-8

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  • DOI: https://doi.org/10.1007/s11095-019-2605-8

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