Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response Evaluation

Background: Venous thromboembolism (VTE) in children occurs with increasing frequency predominantly as a result of hospital-acquired thrombosis leading to a substantial rise in the use of anticoagulant medications in children. Only one anticoagulant (dalteparin, a subcutaneously administered agent) is licensed for use in children, but the evidence to support the use of anticoagulants in children is lacking. While several direct oral anticoagulants have been licensed and are in widespread use in adults, as of yet, none have been licensed for children and child-appropriate formulations are not commercially available. The EINSTEIN-Jr. program is a comprehensive clinical development program aimed at providing data to support the use (and eventual licensure) of rivaroxaban for children with VTE. The recently completed randomized EINSTEIN-Jr. phase 3 study showed similar efficacy and safety for rivaroxaban compared to standard anticoagulation for treatment of pediatric VTE. This abstract reports the results of the dose-exposure-response relationship of rivaroxaban from this study. The pediatric rivaroxaban dosing regimens were established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling and has been previously reported.

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-<30, and <12kg, respectively. In children weighing <12kg, the lower range of the adult exposure range was targeted to avoid excessive concentrations at the end of the dosing interval. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those <20kg. Based on sparse blood sampling, the 24-hour 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, change in thrombus burden at repeat imaging, and bleeding or adverse events. A taste and texture questionnaire was collected from suspension recipients.

Results: Between November, 2014 and September, 2018, a total of 365 children were allocated to receive rivaroxaban in the following age groups: birth-<0.5 years (n=13); 0.5-<2 years (n=21); 2-<6 years (n=44); 6-<12 years (n=65); and 12-<18 years (n=173). Of these, 316 (94.3%) were evaluable for PK analyses. A total of 121 (38.3%) children received the rivaroxaban tablet formulation and 195 (61.7%) the suspension formulation. Symptomatic recurrent VTE occurred in 2 children (0.6%) during rivaroxaban treatment. Repeat imaging outcomes in the asymptomatic children were classified as normalized in 124 (39.2%), improved in 125 (39.6%), no relevant change in 16 (5.1%), and deteriorated in 1 (0.3%). In 48 children (15.2%) the result of repeat imaging was uncertain. No major bleeding events occurred with rivaroxaban treatment, whereas clinically relevant non-major bleeding and trivial bleeding were observed in 10 (3.2%) and 111 (35.1%) children, respectively. With respect to the dose-exposure relationship, the vast majority of the individual values were within the 5^th-95^th percentile for AUC(0-24)_ss, C_max,ss and C_trough,ss (see figure below on the left). With respect to exposure-response relationship, no clustering was observed for any of the PK parameters with respect to efficacy, bleeding (shown in the figure below on the right), or adverse event outcomes. The results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable.

Conclusion: Treatment of children with bodyweight-adjusted rivaroxaban regimens resulted in exposures similar to those previously observed in adults receiving 20 mg once daily dosing and the level of exposure was not related to the efficacy, bleeding, or adverse events. Based on this analysis and in conjunction with the previously demonstrated similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide a new alternative treatment option for VTE in children.

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