Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation
Por:
Young, G, Lensing, A, Monagle, P, Male, C, Thelen, K, Willmann, S, Palumbo, J, Kumar, R, Nurmeev, I, Hege, K, Bajolle, F, Connor, P, Hooimeijer, H, Torres, M, Chan, A, Kenet, G, Holzhauer, S, Santamaria, A, Amedro, P, Beyer-Westendorf, J, Martinelli, I, Massicotte, M, Smith, W, Berkowitz, S, Schmidt, S, Price, V, Prins, M, Kubitza, D and EINSTEIN-Jr Phase 3 Investigators
Publicada:
1 jul 2020
Ahead of Print:
1 jun 2020
Resumen:
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,C-ss] and maximum [C-max,C-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.
Filiaciones:
Young, G:
Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Los Angeles, CA 90007 USA
Lensing, A:
Bayer AG, Wuppertal, Germany
Monagle, P:
Royal Childrens Hosp, Haematol Res Murdoch Childrens Res Inst, Dept Clin Haematol, Parkville, Vic, Australia
Univ Melbourne, Dept Paediat, Parkville, Vic, Australia
Male, C:
Med Univ Vienna, Dept Paediat, Vienna, Austria
Thelen, K:
Bayer AG, Wuppertal, Germany
Willmann, S:
Bayer AG, Wuppertal, Germany
Palumbo, J:
Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA
Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA
Kumar, R:
Ohio State Univ, Nationwide Childrens Hosp, Columbus, OH 43210 USA
Nurmeev, I:
Kazan State Med Univ, Kazan, Russia
Hege, K:
Riley Hosp Children IU Hlth, Indianapolis, IN USA
Bajolle, F:
Univ Paris 05, Sorbonne Paris Cite, M3C Necker Enfants Malad, Paris, France
Connor, P:
Noahs Ark Childrens Hosp Wales, Cardiff, Wales
Hooimeijer, H:
Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Hematol & Oncol, Groningen, Netherlands
Torres, M:
Cook Childrens Med Ctr, Dept Hematol & Oncol, Ft Worth, TX USA
Chan, A:
McMaster Childrens Hosp, Hamilton, ON, Canada
Kenet, G:
Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
Sheba Med Ctr, Israeli Natl Hemophilia Ctr, Amalia Biron Thrombosis Res Inst, Tel Hashomer, Israel
Sheba Med Ctr, Thrombosis Unit, Amalia Biron Thrombosis Res Inst, Tel Hashomer, Israel
Holzhauer, S:
Charite, Dept Pediat Hematol & Oncol, Berlin, Germany
:
Univ Hosp Vall dHebron, Dept Hematol, Hemostasis & Thrombosis Unit, Barcelona, Spain
Amedro, P:
Montpellier Univ Hosp, M3C Reg Reference Ctr, Paediat & Congenital Cardiol Dept, PhyMedExp,INSERM,CNRS, Montpellier, France
Beyer-Westendorf, J:
Kings Coll London, Univ Hosp Carl Gustav Carus Dresden, Div Haematol & Haemostaseol, Dept Med 1,Dept Haematol,Kings Thrombosis Serv, London, England
Martinelli, I:
Fdn IRCCS Ca Granda Osped Maggiore Policlin, A Bianchi Bonomi Hemophilia & Thrombosis Ctr, Milan, Italy
Massicotte, M:
Univ Alberta, Dept Paediat, Edmonton, AB, Canada
Smith, W:
Bayer US LLC, Whippany, NJ USA
Berkowitz, S:
Bayer US LLC, Whippany, NJ USA
Schmidt, S:
Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Gainesville, FL 32611 USA
Price, V:
Dalhousie Univ, IWK Hlth Ctr, Dept Pediat, Div Pediat Hematol Oncol, Halifax, NS, Canada
Prins, M:
Maastricht Univ, Dept Clin Epidemiol & Med Technol Assessment, Med Ctr, Maastricht, Netherlands
Kubitza, D:
Bayer AG, Wuppertal, Germany
Green Submitted, Bronze, Green Published
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