Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

doi:10.1111/jth.14813

Clinical Trial

. 2020 Jul;18(7):1672-1685.

doi: 10.1111/jth.14813. Epub 2020 Jun 4.

Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

Guy Young¹, Anthonie W A Lensing², Paul Monagle^{3

4}, Christoph Male⁵, Kirstin Thelen², Stefan Willmann², Joseph S Palumbo^{6

7}, Riten Kumar⁸, Ildar Nurmeev⁹, Kerry Hege¹⁰, Fanny Bajolle¹¹, Philip Connor¹², Hélène L Hooimeijer¹³, Marcela Torres¹⁴, Anthony K C Chan¹⁵, Gili Kenet^{16

17}, Susanne Holzhauer¹⁸, Amparo Santamaría¹⁹, Pascal Amedro²⁰, Jan Beyer-Westendorf²¹, Ida Martinelli²², M Patricia Massicotte²³, William T Smith²⁴, Scott D Berkowitz²⁴, Stephan Schmidt²⁵, Victoria Price²⁶, Martin H Prins²⁷, Dagmar Kubitza²; EINSTEIN-Jr. Phase 3 Investigators

Affiliations

¹ Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
² Bayer AG, Wuppertal, Germany.
³ Department of Clinical Haematology, Royal Children's Hospital, Haematology Research Murdoch Children's Research Institute, Parkville, Vic., Australia.
⁴ Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
⁵ Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
⁶ Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁸ Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
⁹ Kazan State Medical University, Kazan, Russia.
¹⁰ Riley Hospital For Children at IU Health, Indianapolis, IN, USA.
¹¹ M3C-Necker Enfants malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
¹² The Noah's Ark Children's Hospital for Wales, Cardiff, UK.
¹³ Department of Hematology and Oncology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
¹⁴ Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX, USA.
¹⁵ McMaster Children's Hospital, Hamilton, ON, Canada.
¹⁶ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹⁷ The Israeli National Hemophilia Center and Thrombosis Unit, The Amalia Biron Thrombosis Research Institute, Sheba Medical Center, Tel Hashomer, Israel.
¹⁸ Department of Pediatric Hematology and Oncology, Charité University Medicine, Berlin, Germany.
¹⁹ Hemostasis and Thrombosis Unit, Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.
²⁰ Paediatric and Congenital Cardiology Department, M3C Regional Reference Centre, Montpellier University Hospital, PhyMedExp, INSERM, CNRS, Montpellier, France.
²¹ Division of Haematology and Haemostaseology, Department of Medicine I, Department of Haematology, University Hospital "Carl Gustav Carus" Dresden, King's Thrombosis Service, King's College London, London, UK.
²² A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Italy.
²³ Department of Paediatrics, University of Alberta, Edmonton, AB, Canada.
²⁴ Bayer U.S., LLC, Whippany, NJ, USA.
²⁵ Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, OR, USA.
²⁶ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, NS, Canada.
²⁷ Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, The Netherlands.

PMID: 32246743
DOI: 10.1111/jth.14813

Free article

Clinical Trial

Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

Guy Young et al. J Thromb Haemost. 2020 Jul.

Free article

. 2020 Jul;18(7):1672-1685.

doi: 10.1111/jth.14813. Epub 2020 Jun 4.

Authors

Affiliations

¹ Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
² Bayer AG, Wuppertal, Germany.
³ Department of Clinical Haematology, Royal Children's Hospital, Haematology Research Murdoch Children's Research Institute, Parkville, Vic., Australia.
⁴ Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
⁵ Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
⁶ Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁸ Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
⁹ Kazan State Medical University, Kazan, Russia.
¹⁰ Riley Hospital For Children at IU Health, Indianapolis, IN, USA.
¹¹ M3C-Necker Enfants malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
¹² The Noah's Ark Children's Hospital for Wales, Cardiff, UK.
¹³ Department of Hematology and Oncology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
¹⁴ Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX, USA.
¹⁵ McMaster Children's Hospital, Hamilton, ON, Canada.
¹⁶ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹⁷ The Israeli National Hemophilia Center and Thrombosis Unit, The Amalia Biron Thrombosis Research Institute, Sheba Medical Center, Tel Hashomer, Israel.
¹⁸ Department of Pediatric Hematology and Oncology, Charité University Medicine, Berlin, Germany.
¹⁹ Hemostasis and Thrombosis Unit, Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.
²⁰ Paediatric and Congenital Cardiology Department, M3C Regional Reference Centre, Montpellier University Hospital, PhyMedExp, INSERM, CNRS, Montpellier, France.
²¹ Division of Haematology and Haemostaseology, Department of Medicine I, Department of Haematology, University Hospital "Carl Gustav Carus" Dresden, King's Thrombosis Service, King's College London, London, UK.
²² A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Italy.
²³ Department of Paediatrics, University of Alberta, Edmonton, AB, Canada.
²⁴ Bayer U.S., LLC, Whippany, NJ, USA.
²⁵ Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, OR, USA.
²⁶ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, NS, Canada.
²⁷ Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, The Netherlands.

PMID: 32246743
DOI: 10.1111/jth.14813

Abstract

Background: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling.

Methods: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC_(0-24)ss ] and trough [C_trough,ss ] and maximum [C_max,ss ] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients.

Results: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable.

Discussion: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

Keywords: anticoagulation; bodyweight-adjusted dosing; pediatric patients; pharmacokinetics; rivaroxaban; suspension; venous thromboembolism.

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References

REFERENCES

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.
1. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S.
1. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92.
1. European Medicines Agency. Rivaroxaban paediatric investigation plan. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC5002.... Accessed April 2019.
1. FDA list of pediatric written requests issued. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource.... Accessed April 2019.

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[1] Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.

[2] Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.

[3] Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S.

[4] Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S.

[5] Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92.

[6] Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92.

[7] European Medicines Agency. Rivaroxaban paediatric investigation plan. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC5002.... Accessed April 2019.

[8] European Medicines Agency. Rivaroxaban paediatric investigation plan. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC5002.... Accessed April 2019.

[9] FDA list of pediatric written requests issued. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource.... Accessed April 2019.

[10] FDA list of pediatric written requests issued. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource.... Accessed April 2019.

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Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

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Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation

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