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

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.

• Authors: Guy Young, Anthonie W A Lensing, Paul Monagle, Christoph Male, Kirstin Thelen, Stefan Willmann, Joseph S Palumbo, Riten Kumar, Ildar Nurmeev, Kerry Hege, Fanny Bajolle, Philip Connor, Hélène L Hooimeijer, Marcela Torres, Anthony K C Chan, Gili Kenet, Susanne Holzhauer, Amparo Santamaría, Pascal Amedro, Jan Beyer-Westendorf, Ida Martinelli, M Patricia Massicotte, William T Smith, Scott D Berkowitz, Stephan Schmidt, Victoria Price, Martin H Prins, Dagmar Kubitza, EINSTEIN-Jr. Phase 3 Investigators
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 18 Issue 7 Pg. 1672-1685 (07 2020) ISSN: 1538-7836 [Electronic] England
• PMID: 32246743 (Publication Type: Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 International Society on Thrombosis and Haemostasis.

Chemical References

• Anticoagulants
• Rivaroxaban

Topics

• Adolescent
• Adult
• Anticoagulants (adverse effects)
• Blood Coagulation
• Child
• Child, Preschool
• Hemorrhage (chemically induced)
• Humans
• Infant
• Infant, Newborn
• Rivaroxaban (adverse effects)
• Venous Thromboembolism (diagnosis, drug therapy)