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A novel population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B
  • +12
  • Sjoerd Koopman,
  • Tine Goedhart,
  • Laura Bukkems,
  • Trevor Mulders,
  • Frank Leebeek,
  • Karin Fijnvandraat,
  • Michiel Coppens,
  • Mary Mathias,
  • Peter Collins,
  • Campbell Tait,
  • Nicola Curry,
  • Jeanette Payne,
  • Pratima Crowdary,
  • Marjon Cnossen,
  • Ron Mathot
Sjoerd Koopman
Amsterdam UMC Locatie AMC

Corresponding Author:[email protected]

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Tine Goedhart
Erasmus MC Sophia Children Hospital
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Laura Bukkems
Amsterdam University Medical Centres
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Trevor Mulders
Amsterdam University Medical Centres
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Frank Leebeek
Erasmus MC
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Karin Fijnvandraat
Amsterdam UMC Locatie AMC
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Michiel Coppens
Amsterdam UMC Location AMC Department of Vascular Medicine
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Mary Mathias
Great Ormond Street Hospital for Children NHS Foundation Trust
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Peter Collins
Cardiff University School of Medicine
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Campbell Tait
University of Glasgow
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Nicola Curry
Oxford University Hospitals NHS Foundation Trust Nuffield Orthopaedic Centre
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Jeanette Payne
Sheffield Children's Hospital NHS Foundation Trust
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Pratima Crowdary
Royal Free London NHS Foundation Trust
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Marjon Cnossen
Erasmus MC Sophia Children Hospital
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Ron Mathot
Amsterdam UMC - Locatie AMC
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Abstract

Background Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life (EHL) factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients ≥12 years of age. Aim Assess the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real world data. Methods We collected prospective and retrospective data from patients with haemophilia B (FIX activity level ≤5 IU/dL) treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kingdom (UK)-EHL Outcome Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A novel population PK model was constructed using nonlinear mixed-effects modelling. Results Real world data was obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were <12 years of age. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error (PE) of -48.8%. The novel model showed a lower median PE (3.4%) and better described rFIX-Fc PK, especially for children <12 years of age. In the novel model, an increase in age was correlated with a decrease in clearance (p<0.01). Conclusion The published population PK model significantly underpredicted FIX activity levels. The novel model better describes rFIX-Fc PK, especially for children <12 years of age. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.
25 May 2023Submitted to British Journal of Clinical Pharmacology
26 May 2023Submission Checks Completed
26 May 2023Assigned to Editor
26 May 2023Review(s) Completed, Editorial Evaluation Pending
02 Jun 2023Reviewer(s) Assigned
26 Jun 2023Editorial Decision: Revise Major
24 Jul 20231st Revision Received
24 Jul 2023Submission Checks Completed
24 Jul 2023Assigned to Editor
24 Jul 2023Review(s) Completed, Editorial Evaluation Pending
27 Jul 2023Editorial Decision: Accept