Rivaroxaban for treatment of pediatric venous thromboembolism: An Einstein-Jr phase 3 dose-exposure-response evaluation

G. Young; A.W.A. Lensing; P. Monagle; C. Male; K. Thelen; S. Willmann; J.S. Palumbo; R. Kumar; I. Nurmeev; K. Hege; F. Bajolle; P. Connor; H.L. Hooimeijer; M. Torres; A.K.C. Chan; G. Kenet; S. Holzhauer; A. Santamaria; P. Amedro; J. Beyer-Westendorf; I. Martinelli; M.P. Massicotte; W.T. Smith; S.D. Berkowitz; S. Schmidt; V. Price; M.H. Prins; D. Kubitza; EINSTEIN-Jr Phase 3 Investigators

doi:10.1111/jth.14813

Rivaroxaban for treatment of pediatric venous thromboembolism: An Einstein-Jr phase 3 dose-exposure-response evaluation

G. Young^*, A.W.A. Lensing, P. Monagle, C. Male, K. Thelen, S. Willmann, J.S. Palumbo, R. Kumar, I. Nurmeev, K. Hege, F. Bajolle, P. Connor, H.L. Hooimeijer, M. Torres, A.K.C. Chan, G. Kenet, S. Holzhauer, A. Santamaria, P. Amedro, J. Beyer-WestendorfI. Martinelli, M.P. Massicotte, W.T. Smith, S.D. Berkowitz, S. Schmidt, V. Price, M.H. Prins, D. Kubitza, EINSTEIN-Jr Phase 3 Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 = 20 kg but only predicted in those

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.

Original language	English
Pages (from-to)	1672-1685
Number of pages	14
Journal	Journal of Thrombosis and Haemostasis
Volume	18
Issue number	7
DOIs	https://doi.org/10.1111/jth.14813
Publication status	Published - 1 Jul 2020

Keywords

anticoagulation
antithrombotic therapy
atrial-fibrillation
bodyweight-adjusted dosing
children
definition
disease
pediatric patients
pharmacokinetics
rivaroxaban
suspension
thrombosis
venous thromboembolism
DEFINITION
THROMBOSIS
ATRIAL-FIBRILLATION
CHILDREN
ANTITHROMBOTIC THERAPY
DISEASE

Access to Document

10.1111/jth.14813Licence: Free access - publisher

Cite this

Young, G., Lensing, A. W. A., Monagle, P., Male, C., Thelen, K., Willmann, S., Palumbo, J. S., Kumar, R., Nurmeev, I., Hege, K., Bajolle, F., Connor, P., Hooimeijer, H. L., Torres, M., Chan, A. K. C., Kenet, G., Holzhauer, S., Santamaria, A., Amedro, P., ... EINSTEIN-Jr Phase 3 Investigators (2020). Rivaroxaban for treatment of pediatric venous thromboembolism: An Einstein-Jr phase 3 dose-exposure-response evaluation. Journal of Thrombosis and Haemostasis, 18(7), 1672-1685. https://doi.org/10.1111/jth.14813

@article{9350f763256643cfad97c3105f048487,

title = "Rivaroxaban for treatment of pediatric venous thromboembolism: An Einstein-Jr phase 3 dose-exposure-response evaluation",

abstract = "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 = 20 kg but only predicted in thoseResults 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.",

keywords = "anticoagulation, antithrombotic therapy, atrial-fibrillation, bodyweight-adjusted dosing, children, definition, disease, pediatric patients, pharmacokinetics, rivaroxaban, suspension, thrombosis, venous thromboembolism, DEFINITION, THROMBOSIS, ATRIAL-FIBRILLATION, CHILDREN, ANTITHROMBOTIC THERAPY, DISEASE",

author = "G. Young and A.W.A. Lensing and P. Monagle and C. Male and K. Thelen and S. Willmann and J.S. Palumbo and R. Kumar and I. Nurmeev and K. Hege and F. Bajolle and P. Connor and H.L. Hooimeijer and M. Torres and A.K.C. Chan and G. Kenet and S. Holzhauer and A. Santamaria and P. Amedro and J. Beyer-Westendorf and I. Martinelli and M.P. Massicotte and W.T. Smith and S.D. Berkowitz and S. Schmidt and V. Price and M.H. Prins and D. Kubitza and {EINSTEIN-Jr Phase 3 Investigators}",

year = "2020",

month = jul,

day = "1",

doi = "10.1111/jth.14813",

language = "English",

volume = "18",

pages = "1672--1685",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley",

number = "7",

}

Young, G, Lensing, AWA, Monagle, P, Male, C, Thelen, K, Willmann, S, Palumbo, JS, Kumar, R, Nurmeev, I, Hege, K, Bajolle, F, Connor, P, Hooimeijer, HL, Torres, M, Chan, AKC, Kenet, G, Holzhauer, S, Santamaria, A, Amedro, P, Beyer-Westendorf, J, Martinelli, I, Massicotte, MP, Smith, WT, Berkowitz, SD, Schmidt, S, Price, V, Prins, MH, Kubitza, D & EINSTEIN-Jr Phase 3 Investigators 2020, 'Rivaroxaban for treatment of pediatric venous thromboembolism: An Einstein-Jr phase 3 dose-exposure-response evaluation', Journal of Thrombosis and Haemostasis, vol. 18, no. 7, pp. 1672-1685. https://doi.org/10.1111/jth.14813

TY - JOUR

T1 - Rivaroxaban for treatment of pediatric venous thromboembolism

T2 - An Einstein-Jr phase 3 dose-exposure-response evaluation

AU - Young, G.

AU - Lensing, A.W.A.

AU - Monagle, P.

AU - Male, C.

AU - Thelen, K.

AU - Willmann, S.

AU - Palumbo, J.S.

AU - Kumar, R.

AU - Nurmeev, I.

AU - Hege, K.

AU - Bajolle, F.

AU - Connor, P.

AU - Hooimeijer, H.L.

AU - Torres, M.

AU - Chan, A.K.C.

AU - Kenet, G.

AU - Holzhauer, S.

AU - Santamaria, A.

AU - Amedro, P.

AU - Beyer-Westendorf, J.

AU - Martinelli, I.

AU - Massicotte, M.P.

AU - Smith, W.T.

AU - Berkowitz, S.D.

AU - Schmidt, S.

AU - Price, V.

AU - Prins, M.H.

AU - Kubitza, D.

AU - EINSTEIN-Jr Phase 3 Investigators

PY - 2020/7/1

Y1 - 2020/7/1

N2 - 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 = 20 kg but only predicted in thoseResults 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.

AB - 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 = 20 kg but only predicted in thoseResults 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.

KW - anticoagulation

KW - antithrombotic therapy

KW - atrial-fibrillation

KW - bodyweight-adjusted dosing

KW - children

KW - definition

KW - disease

KW - pediatric patients

KW - pharmacokinetics

KW - rivaroxaban

KW - suspension

KW - thrombosis

KW - venous thromboembolism

KW - DEFINITION

KW - THROMBOSIS

KW - ATRIAL-FIBRILLATION

KW - CHILDREN

KW - ANTITHROMBOTIC THERAPY

KW - DISEASE

U2 - 10.1111/jth.14813

DO - 10.1111/jth.14813

M3 - Article

C2 - 32246743

SN - 1538-7933

VL - 18

SP - 1672

EP - 1685

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 7

ER -