Abstract
Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate 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 treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2–71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of −48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P <.01). Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.
Original language | English |
---|---|
Pages (from-to) | 220-231 |
Number of pages | 12 |
Journal | British journal of clinical pharmacology |
Volume | 90 |
Issue number | 1 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Jan 2024 |
Keywords
- extended half-life
- factor IX
- haemophilia B
- pharmacokinetics
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In: British journal of clinical pharmacology, Vol. 90, No. 1, 01.2024, p. 220-231.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B
AU - Koopman, Sjoerd F.
AU - Goedhart, Tine M. H. J.
AU - Bukkems, Laura H.
AU - Mulders, Trevor M.
AU - Leebeek, Frank W. G.
AU - Fijnvandraat, Karin
AU - Coppens, Michiel
AU - Mathias, Mary
AU - Collins, Peter W.
AU - Tait, R. Campbell
AU - Bagot, Catherine N.
AU - Curry, Nicola
AU - Payne, Jeanette
AU - Chowdary, Pratima
AU - Cnossen, Marjon H.
AU - Mathôt, Ron A. A.
N1 - Funding Information: F.W.G. Leebeek has received unrestricted grants from CSL Behring, Takeda, Sobi and uniQure. He is a consultant for CSL Behring, Takeda, Biomarin and uniQure, of which the fees go to the University. He was DSMB member of a study sponsored by Roche. Funding Information: The SYMPHONY consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals, and translational and fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. To achieve this goal, workpackages have been organized according to 3 themes e.g. Diagnostics (workpackages 3 and 4); Treatment (workpackages 5‐9) and Fundamental Research (workpackages 10–12). This research receives funding from the Netherlands Organisation for Scientific Research (NWO) in the framework of the NWA‐ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project coordinator: Dr. S.H. Reitsma. SYMPHONY consortium: Funding Information: SYMPHONY consortium: The SYMPHONY consortium which aims to orchestrate personalized treatment in patients with bleeding disorders, is a unique collaboration between patients, health care professionals, and translational and fundamental researchers specialized in inherited bleeding disorders, as well as experts from multiple disciplines. It aims to identify best treatment choice for each individual based on bleeding phenotype. To achieve this goal, workpackages have been organized according to 3 themes e.g. Diagnostics (workpackages 3 and 4); Treatment (workpackages 5-9) and Fundamental Research (workpackages 10–12). This research receives funding from the Netherlands Organisation for Scientific Research (NWO) in the framework of the NWA-ORC Call grant agreement NWA.1160.18.038. Principal investigator: Dr. M.H. Cnossen. Project coordinator: Dr. S.H. Reitsma. Beneficiaries of the SYMPHONY consortium: Erasmus University Medical Center-Sophia Children's Hospital, project leadership and coordination; Sanquin Diagnostics; Sanquin Research; Amsterdam University Medical Centers; University Medical Center Groningen; University Medical Center Utrecht; Leiden University Medical Center; Radboud University Medical Center; Netherlands Society of Hemophilia Patients (NVHP); Netherlands Society for Thrombosis and Hemostasis (NVTH); Bayer B.V., CSL Behring B.V., Swedish Orphan Biovitrum (Belgium) BVBA/SPRL. Additional beneficiaries, not included in the SYMPHONY consortium, currently funding parallel projects are: Novonordisk (OPTI-CLOT TARGET), Roche (Partitura), Stichting Haemophilia (patient-reported outcomes project). OPTI-CLOT study group: OPTI-CLOT/To WiN study group aims to implement personalized treatment by pharmacometric-guided dosing of factor concentrates, desmopressin and nonfactor therapies in patients with bleeding disorders. OPTI-CLOT/To WiN Steering Committee, the Netherlands: M.H. Cnossen (principal Investigator & chair OPTI-CLOT-To WiN) and R.A.A. Mathôt (coinvestigator). F.W.G. Leebeek, Rotterdam;, M. Coppens K. Fijnvandraat, Amsterdam; K. Meijer, Groningen, S.E.M. Schols, Nijmegen; H.C.J. Eikenboom, Leiden; R.E.G. Schutgens, Utrecht; F. Heubel-Moenen, Maastricht; L. Nieuwenhuizen, Veldhoven; P. Ypma, The Hague; M.H.E. Driessens, Nijkerk. Trial bureau: I. van Vliet, Rotterdam. Local collaborators the Netherlands: M.J.H.A. Kruip, S. Polinder, Rotterdam; P. Brons, Nijmegen; F.J.M. van der Meer, Leiden; K. Fischer, K. van Galen, Utrecht. Principal investigators and local collaborators in the UK: P. W. Collins, Cardiff; M. Mathias, P. Chowdary, London; D. Keeling, Oxford. OPTI-CLOT-To WiN, DAVID and SYMPHONY PhDs: PhDs: J. Lock, H.C.A.M. Hazendonk, T. Preijers, N.C.B. de Jager, L. Schutte, L.H. Bukkems. PhDs ongoing: M.C.H.J. Goedhart, J.M. Heijdra, L. Romano, W. Al Arashi, M.E. Cloesmeijer, A. Janssen, S.F. Koopman, C. Mussert. Publisher Copyright: © 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2024/1
Y1 - 2024/1
N2 - Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate 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 treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2–71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of −48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P <.01). Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.
AB - Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate 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 treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2–71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of −48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P <.01). Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.
KW - extended half-life
KW - factor IX
KW - haemophilia B
KW - pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85170653705&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bcp.15881
DO - https://doi.org/10.1111/bcp.15881
M3 - Article
C2 - 37567779
SN - 0306-5251
VL - 90
SP - 220
EP - 231
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 1
ER -