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Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein‐Jr phase 3 dose‐exposure‐response evaluation
Author(s) -
Young Guy,
Lensing Anthonie W. A.,
Monagle Paul,
Male Christoph,
Thelen Kirstin,
Willmann Stefan,
Palumbo Joseph S.,
Kumar Riten,
Nurmeev Ildar,
Hege Kerry,
Bajolle Fanny,
Connor Philip,
Hooimeijer Hélène L.,
Torres Marcela,
Chan Anthony K. C.,
Kenet Gili,
Holzhauer Susanne,
Santamaría Amparo,
Amedro Pascal,
BeyerWestendorf Jan,
Martinelli Ida,
Massicotte M. Patricia,
Smith William T.,
Berkowitz Scott D.,
Schmidt Stephan,
Price Victoria,
Prins Martin H.,
Kubitza Dagmar
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14813
Subject(s) - rivaroxaban , medicine , dosing , cmax , adverse effect , tolerability , pharmacokinetics , population , anesthesia , warfarin , environmental health , atrial fibrillation
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.