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Zhu P, Willmann S, Zhou W, et al. Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study. J Clin Pharmacol. 2021;doi: 10.1002/jcph.1966.
Zhu, P., Willmann, S., Zhou, W., Yang, H., Michelson, A. D., McCrindle, B. W., Li, J. S., Harris, K. C., Pina, L. M., Weber, T., Nessel, K., Lesko, L. J., Kubitza, D., & Zannikos, P. (2021). Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study. Journal of clinical pharmacology, . https://doi.org/10.1002/jcph.1966
Zhu, Peijuan, et al. "Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study." Journal of clinical pharmacology vol. (2021). doi: https://doi.org/10.1002/jcph.1966
Zhu P, Willmann S, Zhou W, Yang H, Michelson AD, McCrindle BW, Li JS, Harris KC, Pina LM, Weber T, Nessel K, Lesko LJ, Kubitza D, Zannikos P. Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study. J Clin Pharmacol. 2021 Sep 15; doi: 10.1002/jcph.1966. Epub 2021 Sep 15. PMID: 34524700.
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J Clin Pharmacol. 2021 Sep 15; doi: 10.1002/jcph.1966. Epub 2021 Sep 15.

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

Journal of clinical pharmacology

Peijuan Zhu, Stefan Willmann, Wangda Zhou, Haitao Yang, Alan D Michelson, Brian W McCrindle, Jennifer S Li, Kevin C Harris, Liza Miriam Pina, Traci Weber, Kimberly Nessel, Lawrence J Lesko, Dagmar Kubitza, Peter Zannikos

Affiliations

  1. Janssen Research & Development, LLC, Raritan, New Jersey, USA.
  2. Bayer AG, Pharmaceuticals, Research and Development, Wuppertal, Germany.
  3. Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
  4. Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  5. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  6. Duke University Medical Center, Durham, North Carolina, USA.
  7. Children's Heart Centre, BC Children's Hospital, Vancouver, BC, Canada.
  8. University of Florida College of Pharmacy, Orlando, Florida, USA.

PMID: 34524700 DOI: 10.1002/jcph.1966

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.

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

Keywords: anticoagulants; child; congenital heart disease; pharmacokinetics; thrombosis

References

  1. Manlhiot C, Brandao LR, Kwok J, et al. Thrombotic complications and thromboprophylaxis across all three stages of single ventricle heart palliation. J Pediatr. 2012;161(3):513-519 e513. - PubMed
  2. Balling G, Vogt M, Kaemmerer H, Eicken A, Meisner H, Hess J.Intracardiac thrombus formation after the Fontan operation. J Thorac Cardiovasc Surg. 2000;119(4):745-752. - PubMed
  3. Firdouse M, Agarwal A, Chan AK, Mondal T.Thrombosis and thromboembolic complications in fontan patients: a literature review. Clin Appl Thromb Hemost. 2014;20(5):484-492. - PubMed
  4. Fyfe DA, Kline CH, Sade RM, Gillette PC.Transesophageal echocardiography detects thrombus formation not identified by transthoracic echocardiography after the Fontan operation. J Am Coll Cardiol. 1991;18(7):1733-1737. - PubMed
  5. Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2013;128(24):2622-2703. - PubMed
  6. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S. - PubMed
  7. Lensing AWA, Male C, Young G, et al. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Thromb J. 2018;16:34. - PubMed
  8. Young G, Lensing AWA, Monagle P, Male C, Kubitza D.Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation. Blood. 2019;134(Suppl_1):164-164. - PubMed
  9. Pina LM, Dong X, Zhang L, et al. Rivaroxaban, a direct factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: rationale and design of a prospective, randomized trial (the UNIVERSE study). Am Heart J. 2019;213:97-104. - PubMed
  10. Wallace M. Center variation in patient age and weight at Fontan operation and impact on postoperative outcomes. Ann Thorac Surg. 2010; 91(5):1445-1452. - PubMed
  11. The Society of Thoracic Surgeons (STS) National Database. https://www.sts.org/registries/sts-national-database. Accessed June 30, 2015. - PubMed
  12. Willmann S, Becker C, Burghaus R, et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet. 2014;53(1):89-102. - PubMed
  13. Willmann S, Thelen K, Kubitza D, et al. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study. Thromb J. 2018;16:32. - PubMed
  14. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105(3):444-453. - PubMed
  15. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M.Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873-880. - PubMed
  16. Sun H, Temeck JW, Chambers W, Perkins G, Bonnel R, Murphy D.Extrapolation of efficacy in pediatric drug development and evidence-based medicine: progress and lessons learned. Ther Innov Regul Sci. 2017;2017:1-7. - PubMed
  17. Food and Drug Administration. General clinical pharmacology considerations for pediatric studies for drugs and biological products. https://www.fda.gov/media/90358/download. Accessed September 27, 2021. - PubMed
  18. Willmann S, Zhang L, Frede M, et al. Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations. CPT Pharmacometrics Syst Pharmacol. 2018;7(5):309-320. - PubMed
  19. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G.Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-421. - PubMed
  20. Mueck W, Stampfuss J, Kubitza D, Becka M.Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1-16. - PubMed
  21. Monagle P, Lensing AWA, Thelen K, et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol. 2019;6(10):e500-e509. - PubMed
  22. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006;4(1):121-128. - PubMed
  23. Turpie AG, Fisher WD, Bauer KA, et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost. 2005;3(11):2479-2486. - PubMed
  24. Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA.Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017;151(1):127-138. - PubMed
  25. Kubitza D, Willmann S, Becka M, et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study. Thromb J. 2018;16:31. - PubMed
  26. Germovsek E, Barker CIS, Sharland M, Standing JF. Pharmacokinetic-pharmacodynamic modeling in pediatric drug development, and the importance of standardized scaling of clearance. Clin Pharmacokinet. 2019;58(1):39-52. - PubMed
  27. Barrett JS, Bucci-Rechtweg C, Amy Cheung SY, et al. Pediatric extrapolation in type 2 diabetes: future implications of a workshop. Clin Pharmacol Ther. 2020;108(1):29-39. - PubMed

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