Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study
Dagmar Kubitza, Stefan Willmann, Michael Becka, Kirstin Thelen, Guy Young, Leonardo R Brandão, Paul Monagle, Christoph Male, Anthony Chan, Gili Kennet, Ida Martinelli, Paola Saracco, Anthonie W A Lensing, Dagmar Kubitza, Stefan Willmann, Michael Becka, Kirstin Thelen, Guy Young, Leonardo R Brandão, Paul Monagle, Christoph Male, Anthony Chan, Gili Kennet, Ida Martinelli, Paola Saracco, Anthonie W A Lensing
Abstract
Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.
Methods: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.
Results: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.
Conclusions: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.
Trial registration: ClinicalTrials.gov number, NCT01145859.
Keywords: Developmental hemostasis; Pharmacodynamics; Pharmacokinetics; Rivaroxaban; Venous thromboembolism.
Conflict of interest statement
The protocol was approved by the Institutional Review Board or Ethics Committee of each participating center, if required, and de-identified data was retrieved.Not applicable.DK, SW, MB, KT and AWAL are employees of Bayer. GY, AC, PS, and PM have no competing to report. LRB has received research funds from Sanofi Aventis, and has received honoraria from Bayer and from Boehringer Ingelheim. CM has received honoraria from Bayer AG, Boehringer Ingelheim, and Bristol-Myers Squibb. GK has received honoraria from OPKO biologics, Bayer, Pfizer, CSL, Alnylam, Shire and Roche. IM has received consultancy fees from Bayer.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Figures
References
- Prins MH, Lensing AWA, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21. doi: 10.1186/1477-9560-11-21.
- Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas. Blood Rev. 2010;24:63–68. doi: 10.1016/j.blre.2009.12.001.
- Attard C, Monagle P, Kubitza D, Ignjatovic V. The in vitro anticoagulant effect of rivaroxaban in children. Thromb Res. 2012;130:804–807. doi: 10.1016/j.thromres.2012.07.009.
- Attard C, Monagle P, Kubitza D, Ignjatovic V. The in-vitro anticoagulant effect of rivaroxaban in neonates. Blood Coagul Fibrinolysis. 2014;25:237–240. doi: 10.1097/MBC.0000000000000033.
- Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology-drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–1167. doi: 10.1056/NEJMra035092.
- Willmann S, Becker C, Burghaus R, Coboeken K, Edginton A, Lippert J, et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet. 2014;53:89–102. doi: 10.1007/s40262-013-0090-5.
- Bayer AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2018.
- Rohde G. Determination of rivaroxaban – a novel, oral, direct factor Xa inhibitor – in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;872:43–50. doi: 10.1016/j.jchromb.2008.07.015.
- Willmann S, Thelen K, Kubitza D, Lensing AWA, Frede M, Coboeken K, et al. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling – an EINSTEIN JUNIOR phase I study. Thrombosis J. 2018. 10.1186/s12959-018-0185-1.
- Yee DL, O'Brien SH, Young G. Pharmacokinetics and pharmacodynamics of anticoagulants in paediatric patients. Clin Pharmacokinet. 2013;52:967–980. doi: 10.1007/s40262-013-0094-1.
- Corbella E, Miragliotta G, Masperi R, Villa S, Bini A, de Gaetano G, et al. Platelet aggregation and antithrombin III levels in diabetic children. Haemostasis. 1979;8:30–37.
- Fukui H, Taniguchi A, Sakamoto S, Kawahara S, Matsunaga T, Taira K, et al. Antithrombin III in children with various renal diseases. Pediatr Nephrol. 1989;3:144–148. doi: 10.1007/BF00852896.
- Singh RR, Gupte-Singh KR, Wilson JP, Moffett BS. Adherence to anticoagulant therapy in pediatric patients hospitalized with pulmonary embolism or deep vein thrombosis: a retrospective cohort study. Clin Appl Thromb Hemost. 2016;22:260–264. doi: 10.1177/1076029615601493.
- Halton JM, Lehr T, Cronin L, Lobmeyer MT, Haertter S, Belletrutti M, et al. Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study. Thromb Haemost. 2016;116:461–471. doi: 10.1160/TH15-04-0275.
- Halton JML, Albisetti M, Biss B, Bomgaars L, Brueckmann M, Gropper S, et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost. 2017;15:2147–2157. doi: 10.1111/jth.13847.
- Halton JML, Picard AC, Harper R, Huang F, Brueckmann M, Gropper S, et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of dabigatran etexilate oral liquid formulation in infants with venous thromboembolism. Thromb Haemost. 2017;117:2168–2175. doi: 10.1160/TH17-06-0429.
- Young G, Yee DL, O'Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer. 2011;57:1049–1054. doi: 10.1002/pbc.23011.
- Young G, Tarantino MD, Wohrley J, Weber LC, Belvedere M, Nugent DJ. Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost. 2007;5:1654–1659. doi: 10.1111/j.1538-7836.2007.02623.x.
- O'Brien SH, Yee DL, Lira J, Goldenberg NA, Young G. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis. J Thromb Haemost. 2015;13:1615–1622. doi: 10.1111/jth.13057.
- Forbes TJ, Hijazi ZM, Young G, Ringewald JM, Aquino PM, Vincent RN, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheter Cardiovasc Interv. 2011;77:671–679. doi: 10.1002/ccd.22817.
- Young G, Boshkov LK, Sullivan JE, Raffini LJ, Cox DS, Boyle DA, et al. Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer. 2011;56:1103–1109. doi: 10.1002/pbc.22852.
- Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 2011;89:46–53. doi: 10.2471/BLT.10.080010.
Source: PubMed