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

• Main Authors: Harris, K.C (Author), Kubitza, D. (Author), Lesko, L.J (Author), Li, J.S (Author), McCrindle, B.W (Author), Michelson, A.D (Author), Nessel, K. (Author), Pina, L.M (Author), Weber, T. (Author), Willmann, S. (Author), Yang, H. (Author), Zannikos, P. (Author), Zhou, W. (Author), Zhu, P. (Author)
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2022
• Subjects: acetylsalicylic acid; activated partial thromboplastin time; adult; anticoagulant agent; Anticoagulants; Area Under Curve; area under the curve; Article; biological model; blood clotting factor 10a inhibitor; body weight; Body Weights and Measures; child; Child; Child, Preschool; clinical trial; controlled study; drug dose regimen; drug efficacy; drug safety; drug tolerability; female; Female; Fontan procedure; Fontan Procedure; groups by age; heart single ventricle; heparin; human; Humans; low molecular weight heparin; major clinical study; male; Male; maximum plasma concentration; Models, Biological; morphometry; multicenter study; open study; partial thromboplastin time; Partial Thromboplastin Time; pharmacokinetic parameters; phase 3 clinical trial; plasma concentration-time curve; postoperative thrombosis; prediction; preschool child; procedures; Prospective Studies; prospective study; prothrombin time; Prothrombin Time; quantitative analysis; randomized controlled trial; rivaroxaban; Rivaroxaban; school child; thrombosis; Thrombosis; thrombosis prevention; trough concentration
• Online Access: View Fulltext in Publisher
• Physical Description: 12
• ISBN: 00912700 (ISSN)
• DOI: 10.1002/jcph.1966

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. © 2021 Janssen Research and Development LLC. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology