Guy Young1, Anthonie W A Lensing2, Paul Monagle3,4, Christoph Male5, Kirstin Thelen2, Stefan Willmann2, Joseph S Palumbo6,7, Riten Kumar8, Ildar Nurmeev9, Kerry Hege10, Fanny Bajolle11, Philip Connor12, Hélène L Hooimeijer13, Marcela Torres14, Anthony K C Chan15, Gili Kenet16,17, 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. 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.
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 [Ctrough,ss ] and maximum [Cmax,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.
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 [Ctrough,ss ] and maximum [Cmax,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.
Authors: Philip Connor; Mayte Sánchez van Kammen; Anthonie W A Lensing; Elizabeth Chalmers; Krisztián Kállay; Kerry Hege; Paolo Simioni; Tina Biss; Fanny Bajolle; Damien Bonnet; Sebastian Grunt; Riten Kumar; Olga Lvova; Rukhmi Bhat; An Van Damme; Joseph Palumbo; Amparo Santamaria; Paola Saracco; Jeanette Payne; Susan Baird; Kamar Godder; Veerle Labarque; Christoph Male; Ida Martinelli; Michelle Morales Soto; Jayashree Motwani; Sanjay Shah; Helene L Hooimeijer; Martin H Prins; Dagmar Kubitza; William T Smith; Scott D Berkowitz; Akos F Pap; Madhurima Majumder; Paul Monagle; Jonathan M Coutinho Journal: Blood Adv Date: 2020-12-22
Authors: Katharina Thom; Anthonie W A Lensing; Ildar Nurmeev; Fanny Bajolle; Damien Bonnet; Gili Kenet; M Patricia Massicotte; Zeynep Karakas; Joseph S Palumbo; Paola Saracco; Pascal Amedro; Juan Chain; Anthony K Chan; Takanari Ikeyama; Joyce C M Lam; Cynthia Gauger; Ákos Ferenc Pap; Madhurima Majumder; Dagmar Kubitza; William T Smith; Scott D Berkowitz; Martin H Prins; Paul Monagle; Guy Young; Christoph Male Journal: Blood Adv Date: 2020-10-13