Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study
| Autor: | Brian W. McCrindle, Peijuan Zhu, Alan D. Michelson, Traci Weber, Lawrence J. Lesko, Stefan Willmann, Haitao Yang, Dagmar Kubitza, Jennifer S. Li, Liza Miriam Pina, Kevin C. Harris, Wangda Zhou, Kimberly Nessel, Peter Zannikos |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Physiologically based pharmacokinetic modelling Pediatrics medicine.medical_specialty Phases of clinical research Fontan Procedure Models Biological Pharmacokinetics Rivaroxaban Medicine Humans Pharmacology (medical) Body Weights and Measures Prospective Studies Child Pharmacology Prothrombin time medicine.diagnostic_test business.industry Anticoagulants Thrombosis Regimen Drug development Pharmacodynamics Area Under Curve Child Preschool Prothrombin Time Female Partial Thromboplastin Time business medicine.drug |
| Zdroj: | Journal of clinical pharmacology. 62(2) |
| ISSN: | 1552-4604 |
| Popis: | Thrombosis remains an important complication for children with single ventricle physiology post-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 utilizing a model-informed drug development approach. A physiologically based pharmacokinetic (PBPK) 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 3 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 UNIVERSE. The safety and efficacy in the rivaroxaban group were compared to those in the acetylsalicylic acid group for 12 months. Pharmacodynamic endpoints were assessed in both parts of the study. Rivaroxaban exposures achieved in Part 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 PBPK 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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