Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

Introduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG po...

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Autores: Eichler, Hermann, Angchaisuksiri, Pantep, Kavakli, Kaan, Knoebl, Paul, Windyga, Jerzy, Jiménez Yuste, Víctor Manuel, Delff, Philip Harder, Chowdary, Pratima
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/692142
Acceso en línea:http://hdl.handle.net/10486/692142
https://dx.doi.org/10.1111/hae.13627
Access Level:acceso abierto
Palabra clave:Concizumab
Haemophilia
Modelling
Pharmacodynamics
Pharmacokinetics
Phase 1
Medicina
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spelling Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b dataEichler, HermannAngchaisuksiri, PantepKavakli, KaanKnoebl, PaulWindyga, JerzyJiménez Yuste, Víctor ManuelDelff, Philip HarderChowdary, PratimaConcizumabHaemophiliaModellingPharmacodynamicsPharmacokineticsPhase 1MedicinaIntroduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. Aim: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. Methods: Free TFPI predictions were generated using an estimated concizumab‐free TFPI exposure‐response (Emax) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. Results: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re‐established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab‐free TFPI and concizumab‐TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once‐daily dosing would minimize within‐patient concizumab PK variability.Novo NordiskWileyDepartamento de MedicinaFacultad de MedicinaInstituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ)20192019-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/692142https://dx.doi.org/10.1111/hae.13627reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6921422026-06-23T12:46:27Z
dc.title.none.fl_str_mv Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
title Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
spellingShingle Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
Eichler, Hermann
Concizumab
Haemophilia
Modelling
Pharmacodynamics
Pharmacokinetics
Phase 1
Medicina
title_short Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
title_full Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
title_fullStr Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
title_full_unstemmed Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
title_sort Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data
dc.creator.none.fl_str_mv Eichler, Hermann
Angchaisuksiri, Pantep
Kavakli, Kaan
Knoebl, Paul
Windyga, Jerzy
Jiménez Yuste, Víctor Manuel
Delff, Philip Harder
Chowdary, Pratima
author Eichler, Hermann
author_facet Eichler, Hermann
Angchaisuksiri, Pantep
Kavakli, Kaan
Knoebl, Paul
Windyga, Jerzy
Jiménez Yuste, Víctor Manuel
Delff, Philip Harder
Chowdary, Pratima
author_role author
author2 Angchaisuksiri, Pantep
Kavakli, Kaan
Knoebl, Paul
Windyga, Jerzy
Jiménez Yuste, Víctor Manuel
Delff, Philip Harder
Chowdary, Pratima
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
Instituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ)
dc.subject.none.fl_str_mv Concizumab
Haemophilia
Modelling
Pharmacodynamics
Pharmacokinetics
Phase 1
Medicina
topic Concizumab
Haemophilia
Modelling
Pharmacodynamics
Pharmacokinetics
Phase 1
Medicina
description Introduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. Aim: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. Methods: Free TFPI predictions were generated using an estimated concizumab‐free TFPI exposure‐response (Emax) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. Results: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re‐established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab‐free TFPI and concizumab‐TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once‐daily dosing would minimize within‐patient concizumab PK variability.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-01-01
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 http://hdl.handle.net/10486/692142
https://dx.doi.org/10.1111/hae.13627
url http://hdl.handle.net/10486/692142
https://dx.doi.org/10.1111/hae.13627
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
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
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
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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