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

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dc.contributor.author Eichler, Hermann
dc.contributor.author Angchaisuksiri, Pantep
dc.contributor.author Kavakli, Kaan
dc.contributor.author Knoebl, Paul
dc.contributor.author Windyga, Jerzy
dc.contributor.author Jiménez‐Yuste, Víctor
dc.contributor.author Delff, Philip Harder
dc.contributor.author Chowdary, Pratima
dc.contributor.other UAM. Departamento de Medicina es_ES
dc.contributor.other Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ) es_ES
dc.date.accessioned 2020-10-05T10:16:58Z
dc.date.available 2020-10-05T10:16:58Z
dc.date.issued 2019
dc.identifier.citation Haemophilia 25 (2019): 60–66 en_US
dc.identifier.issn 1351-8216 (print) es_ES
dc.identifier.issn 1365-2516 (online) es_ES
dc.identifier.uri http://hdl.handle.net/10486/692142
dc.description.abstract 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. en_US
dc.description.sponsorship Novo Nordisk en_US
dc.format.extent 7 pag. es_ES
dc.format.mimetype application/pdf en_US
dc.language.iso eng en_US
dc.publisher Wiley en_US
dc.relation.ispartof Haemophilia en_US
dc.rights © 2018 The Author(s) en_US
dc.subject.other Concizumab en_US
dc.subject.other Haemophilia en_US
dc.subject.other Modelling en_US
dc.subject.other Pharmacodynamics en_US
dc.subject.other Pharmacokinetics en_US
dc.subject.other Phase 1 en_US
dc.title Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion https://doi.org/10.1111/hae.13627 es_ES
dc.identifier.doi 10.1111/hae.13627 es_ES
dc.identifier.publicationfirstpage 60 es_ES
dc.identifier.publicationissue 25 es_ES
dc.identifier.publicationlastpage 66 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento – NoComercial – SinObraDerivada es_ES
dc.rights.accessRights openAccess en
dc.authorUAM Jiménez Yuste, Víctor Manuel (261024)


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