Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study

Abstract

Thrombosis remains an important complication for children with single-ventricle physiology following the Fontan procedure, and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined using a model-informed drug development approach. A physiologically based pharmacokinetic rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults. This regimen was used in an open-label, multicenter phase III study, which investigated the use of rivaroxaban for thromboprophylaxis in post-Fontan patients 2 to 8 years of age. The pharmacokinetics (PK) of rivaroxaban was assessed in part A (n = 12) and in part B (n = 64) of the UNIVERSE study. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic end points were assessed in both parts of the study. Rivaroxaban exposures achieved in parts A and B were similar to the adult reference exposures. Prothrombin time also showed similarity to the adult reference.Exposure-response analysis did not identify a quantitative relationship between rivaroxaban exposures and efficacy/safety outcomes within the observed exposure ranges. A body weight-based dose regimen selected by physiologically based pharmacokinetic modeling was shown in the UNIVERSE study to be appropriate for thromboprophylaxis in the post-Fontan pediatric population. Model-based dose selection can support pediatric drug development and bridge adult dose data to pediatrics, thereby obviating the need for dose-finding studies in pediatric programs.

Model‐informed bridging of rivaroxaban doses for thromboprophylaxis in pediatric patients aged 9 years and older with congenital heart disease

“…for the prevention of thromboembolic events after major orthopedic surgery, applying a regimen of two times a day in children 9,20 . The UNIVERSE study confirmed that the body weight–adjusted dose regimen in post‐Fontan patients between 2 and 8 years of age resulted in rivaroxaban exposure that matched the adult reference exposures at 10 mg o.d 20 . The post‐Fontan patients who received rivaroxaban had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group 21 .…”

“…The bridging approach made use of (i) available dose-exposure data of rivaroxaban from another pediatric program, EINSTEIN-Jr, which investigated rivaroxaban for the treatment of acute VTE in children between 0 and 18 years of age [1][2][3][4][5] and (ii) preexisting PBPK and popPK models of rivaroxaban in pediatric patients. [6][7][8]20 At first, the predictive performances of the Fontan-PBPK model 20 and the EINSTEIN-Jr popPK model 8 for the UNIVERSE data were retrospectively assessed. Both models showed a tendency toward S1).…”

“…To close this gap, a model‐informed bridging approach employing PBPK as well as popPK modeling and simulation was developed to extrapolate the rivaroxaban dose–exposure relationship for thromboprophylaxis that was established in the UNIVERSE study for post‐Fontan patients in the age range between 2 and 8 years to post‐Fontan patients aged 9–18 years. The bridging approach made use of (i) available dose–exposure data of rivaroxaban from another pediatric program, EINSTEIN‐Jr, which investigated rivaroxaban for the treatment of acute VTE in children between 0 and 18 years of age 1–5 and (ii) preexisting PBPK and popPK models of rivaroxaban in pediatric patients 6–8,20 . At first, the predictive performances of the Fontan‐PBPK model 20 and the EINSTEIN‐Jr popPK model 8 for the UNIVERSE data were retrospectively assessed.…”

“…Instead, suitable rivaroxaban doses for thromboprophylaxis in post-Fontan children aged 9 years and older or weighing ≥30 kg were derived by a bridging approach using rivaroxaban PBPK and popPK models based on data from adults and children. [6][7][8]20 The aim of this article is to report the results of the model-based bridging concept that was designed to obtain suitable rivaroxaban doses for thromboprophylaxis in pediatric CHD patients aged 9 years and older after the Fontan procedure.…”

“…The body weight–adjusted rivaroxaban dosing regimen that was applied in the UNIVERSE study was derived using a pediatric Fontan‐PBPK model as described in Zhu et al 20 Targeted exposure for thromboprophylaxis in children with CHD was the daily exposure (measured by the area under the plasma concentration–time curve over 24 h at steady state [AUC (0–24 h),ss ]) observed in adult patients receiving 10 mg rivaroxaban o.d. for the prevention of thromboembolic events after major orthopedic surgery, applying a regimen of two times a day in children 9,20 . The UNIVERSE study confirmed that the body weight–adjusted dose regimen in post‐Fontan patients between 2 and 8 years of age resulted in rivaroxaban exposure that matched the adult reference exposures at 10 mg o.d 20 .…”