Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks

Background Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4)....

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Autores: Kiialainen, Anna, Adamkewicz, JoanneI, Petry, Claire, Oldenburg, Johannes, Pipe, Steven W., Young, Guy, Mahlangu, Johnny, Lehle, Michaela, Niggli, Markus, Castaman, Giancarlo, Jiménez Yuste, Víctor Manuel, Shima, Midori, Négrier, Claude, Schmitt, Christophe
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:dnet:biblosearchi::e992ff5bb1841fd5e9f0a02b2677face
Acceso en línea:https://hdl.handle.net/10486/762240
https://dx.doi.org/10.1016/j.rpth.2023.102306
Access Level:acceso abierto
Palabra clave:biomarkers
emicizumab
hemophilia A
pharmacodynamics
pharmacokinetics
Medicina
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spelling Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeksKiialainen, AnnaAdamkewicz, JoanneIPetry, ClaireOldenburg, JohannesPipe, Steven W.Young, GuyMahlangu, JohnnyLehle, MichaelaNiggli, MarkusCastaman, GiancarloJiménez Yuste, Víctor ManuelShima, MidoriNégrier, ClaudeSchmitt, Christophebiomarkersemicizumabhemophilia ApharmacodynamicspharmacokineticsMedicinaBackground Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). Objectives Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. Methods Participants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. Results Emicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). Conclusion In HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkersThe HAVEN studies were funded by F. Hoffmann-La Roche Ltd, Switzerland; Chugai Pharmaceutical Co., Ltd. Third party editorial assistance, under the direction of all authors, was provided by Paige Phillips and Katie Smith of Ashfield MedComms, an Inizio company and was funded by F. Hoffmann-La Roche LtdElsevierFacultad de MedicinaDepartamento de Medicina20242024-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/762240https://dx.doi.org/10.1016/j.rpth.2023.10230638282901reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:biblosearchi::e992ff5bb1841fd5e9f0a02b2677face2026-06-23T12:46:27Z
dc.title.none.fl_str_mv Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
title Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
spellingShingle Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
Kiialainen, Anna
biomarkers
emicizumab
hemophilia A
pharmacodynamics
pharmacokinetics
Medicina
title_short Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
title_full Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
title_fullStr Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
title_full_unstemmed Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
title_sort Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks
dc.creator.none.fl_str_mv Kiialainen, Anna
Adamkewicz, JoanneI
Petry, Claire
Oldenburg, Johannes
Pipe, Steven W.
Young, Guy
Mahlangu, Johnny
Lehle, Michaela
Niggli, Markus
Castaman, Giancarlo
Jiménez Yuste, Víctor Manuel
Shima, Midori
Négrier, Claude
Schmitt, Christophe
author Kiialainen, Anna
author_facet Kiialainen, Anna
Adamkewicz, JoanneI
Petry, Claire
Oldenburg, Johannes
Pipe, Steven W.
Young, Guy
Mahlangu, Johnny
Lehle, Michaela
Niggli, Markus
Castaman, Giancarlo
Jiménez Yuste, Víctor Manuel
Shima, Midori
Négrier, Claude
Schmitt, Christophe
author_role author
author2 Adamkewicz, JoanneI
Petry, Claire
Oldenburg, Johannes
Pipe, Steven W.
Young, Guy
Mahlangu, Johnny
Lehle, Michaela
Niggli, Markus
Castaman, Giancarlo
Jiménez Yuste, Víctor Manuel
Shima, Midori
Négrier, Claude
Schmitt, Christophe
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Facultad de Medicina
Departamento de Medicina
dc.subject.none.fl_str_mv biomarkers
emicizumab
hemophilia A
pharmacodynamics
pharmacokinetics
Medicina
topic biomarkers
emicizumab
hemophilia A
pharmacodynamics
pharmacokinetics
Medicina
description Background Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). Objectives Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. Methods Participants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. Results Emicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). Conclusion In HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-01-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10486/762240
https://dx.doi.org/10.1016/j.rpth.2023.102306
38282901
url https://hdl.handle.net/10486/762240
https://dx.doi.org/10.1016/j.rpth.2023.102306
identifier_str_mv 38282901
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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