Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation.
anticoagulation
bodyweight-adjusted dosing
pediatric patients
pharmacokinetics
rivaroxaban
suspension
venous thromboembolism
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
24
12
2019
revised:
04
03
2020
accepted:
23
03
2020
pubmed:
5
4
2020
medline:
15
5
2021
entrez:
5
4
2020
Statut:
ppublish
Résumé
Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.
Sections du résumé
BACKGROUND
Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling.
METHODS
Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC
RESULTS
Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable.
DISCUSSION
Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.
Identifiants
pubmed: 32246743
doi: 10.1111/jth.14813
pii: S1538-7836(22)01329-0
doi:
Substances chimiques
Anticoagulants
0
Rivaroxaban
9NDF7JZ4M3
Types de publication
Clinical Trial, Phase III
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1672-1685Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
Références
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.
Monagle P, Chan AK, 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.
Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92.
European Medicines Agency. Rivaroxaban paediatric investigation plan. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500232013.pdf. Accessed April 2019.
FDA list of pediatric written requests issued. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm050002.htm. Accessed April 2019.
Male C, Lensing AWA, Palumbo J, et al. Randomised controlled trial of rivaroxaban compared to standard anticoagulants for the treatment of acute venous thromboembolism in children. Lancet Haematol. 2020;7(1):e18-e27.
Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50:675-686.
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
Prins MH, Lensing AW, Bauersachs R, 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.
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.
Willmann S, Becker C, Burghaus R, et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet. 2014;53:89-102.
Kubitza D, Willmann S, Becka M, et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Junior phase I study. Thromb J. 2018;16:31.
Monagle P, Lensing AWA, Thelen K, et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicenter, single-arm, phase 2 studies. Lancet Haematol. 2019;6:e500-e509.
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.
Chan A, Lensing AW, Kubitza D, et al. Clinical presentation and therapeutic management of venous thrombosis in young children: a retrospective analysis. Thromb J. 2018;16:29.
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692-694.
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:2119-2126.
Willmann S, Zhang L, Frede M, et al. Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations. CPT Pharmacometrics Syst Pharmacol. 2018;5:309-320.
Standing JF, Tuleu C. Paediatric formulations - getting to the heart of the problem. Int J Pharm. 2005;300:56-66.
Richey RH, Shah UU, Peak M, et al. Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatr. 2013;13:81-88.
Richey RH, Hughes C, Craig JV, Shaha UU, Ford JL. A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice. Int J Pharm. 2017;518:155-166.
Hart D, Bossert E. Self-reported fears of hospitalized school-age children. J Pediatr Nurs. 1994;2:83-90.
Kortesluoma RL, Nikkonen M. ‘The most disgusting ever’: children's descriptions and views of the purpose of pain. J Child Health Care. 2006;10:213-227.