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Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study
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. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278136/ https://www.ncbi.nlm.nih.gov/pubmed/30534008 http://dx.doi.org/10.1186/s12959-018-0185-1 |
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author | Willmann, Stefan Thelen, Kirstin Kubitza, Dagmar Lensing, Anthonie W. A. Frede, Matthias Coboeken, Katrin Stampfuss, Jan Burghaus, Rolf Mück, Wolfgang Lippert, Jörg |
author_facet | Willmann, Stefan Thelen, Kirstin Kubitza, Dagmar Lensing, Anthonie W. A. Frede, Matthias Coboeken, Katrin Stampfuss, Jan Burghaus, Rolf Mück, Wolfgang Lippert, Jörg |
author_sort | Willmann, Stefan |
collection | PubMed |
description | 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. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed. METHODS: We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE. RESULTS: PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions. CONCLUSIONS: These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010. |
format | Online Article Text |
id | pubmed-6278136 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62781362018-12-10 Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study Willmann, Stefan Thelen, Kirstin Kubitza, Dagmar Lensing, Anthonie W. A. Frede, Matthias Coboeken, Katrin Stampfuss, Jan Burghaus, Rolf Mück, Wolfgang Lippert, Jörg Thromb J Research 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. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed. METHODS: We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE. RESULTS: PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions. CONCLUSIONS: These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010. BioMed Central 2018-12-04 /pmc/articles/PMC6278136/ /pubmed/30534008 http://dx.doi.org/10.1186/s12959-018-0185-1 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Willmann, Stefan Thelen, Kirstin Kubitza, Dagmar Lensing, Anthonie W. A. Frede, Matthias Coboeken, Katrin Stampfuss, Jan Burghaus, Rolf Mück, Wolfgang Lippert, Jörg Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title | Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title_full | Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title_fullStr | Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title_full_unstemmed | Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title_short | Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study |
title_sort | pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an einstein-jr phase i study |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278136/ https://www.ncbi.nlm.nih.gov/pubmed/30534008 http://dx.doi.org/10.1186/s12959-018-0185-1 |
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