Safety, efficacy and PK/PD of rivaroxaban tablets in children with VTE. An Einstein Junior phase II evaluation

Abstract

Background: Rivaroxaban is being developed for VTE treatment in children, targeting the exposure of young adults treated with rivaroxaban 20 mg once-daily. Aims: To investigate the safety and efficacy of rivaroxaban tablets for VTE treatment and to characterize its PK/PD profile. Methods: Children 6-18yrs with VTE who completed ≥ 2 months of anticoagulation received 30 days of body weight-adjusted once-daily rivaroxaban tablets at a 20 mg equivalent dose, based on physiologically-based PK (PBPK) modeling predictions and Phase I data. Repeat imaging was performed at Day 30 and compared to baseline. PK/PD samples were taken on Day 15 and Day 31. PK results were compared with the pediatric PBPK model predictions and with the adult reference population of VTE patients treated with rivaroxaban 20 mg once-daily. PD results were compared to an adult VTE treatment population. Results: 24 children (54 sites/10 countries) were enrolled (12-18yrs, n= 11; 6-12yrs, n= 13). No major bleeding or recurrent VTE occurred. Repeat imaging was improved in 94%. Individual plasma concentrations, as well as AUC, Cmax and Ctrough at steady state, were in the prediction range of the PBPK model and the adult reference range of VTE patients. Children < 30 kg tended to have a Ctrough at the lower end of values observed in adults. Individual values for PT/aPTT were covered by the adult reference range and for both a linear correlation between change from baseline and plasma concentrations was confirmed. A linear relation of anti-factor Xa activity and plasma concentration was observed. Conclusions: 30 days with once-daily rivaroxaban tablets, at a dose targeting the exposure with rivaroxaban 20 mg once-daily in adults, was safe and efficacious. PK/PD profiles were as predicted. However, Ctrough levels were at the lower end of the adult distribution in children < 30 kg, suggesting they require a twice-daily rivaroxaban regimen. Our results need confirmation in the Einstein Junior Phase III study.L6241581612018-10-09 <br />