@article{36935850a691488584919540454a24d2,
title = "A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients",
abstract = "Background {\^a}The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods {\^a}Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results {\^a}A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI:-9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. Conclusion {\^a}We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.",
keywords = "child, pharmacokinetics, population, recombinant factor VIII-Fc, validation",
author = "{for UK-EHL Outcomes Registry OPTI-CLOT Collaboration} and Bukkems, {Laura H.} and Heijdra, {Jessica M.} and Mary Mathias and Collins, {Peter W.} and Hay, {Charles R. M.} and Tait, {Robert C.} and Sarah Mangles and Bethan Myers and G. Evans and Benjamin Bailiff and Nicola Curry and Jeanette Payne and Steve Austin and Goedhart, {Tine M. H. J.} and Leebeek, {Frank W. G.} and Karina Meijer and Karin Fijnvandraat and Pratima Chowdary and Math{\^o}t, {Ron A. A.} and Cnossen, {Marjon H.}",
note = "Funding Information: This particular study was funded by the Dutch Innovation fund, which supplied funding to innovate current hemophilia treatment. Funding Information: J.M.H. has received a grant from CSL Behring outside the submitted work. M.M. has received consultancy fees from Takeda, Bayer, Roche Novo Nordisk, Sobi and Freeline and gave advisory board input to Takeda, Travel support form Takeda, CSL, Novo Nordisk and Roche. P.W.C. has received research support from CSL Behring and consultancy fees from Sobi, Roche and Bayer. R.C. Tait has received consultancy fees from Bayer Healthcare, Pfizer, Shire, NovoNor-disk, Sanofi, Sobi and Daiichi-Sankyo, and travel grants from Bayer Healthcare, NovoNordisk and CSL Behring. S. M. has received consultancies from Novonordisk, Roche, Pfizer and Takeda, and funding for travel/conference registration from Octapharma and Sobi. B.M. has received financial support to attend meetings by SOBI and Amgen and gave lectures for Pfizer over the last year. F.W.G.L. has received unrestricted research grants from CSL Behring and Shireoutside the submitted work, and is consultant for Shire, uniQureand Novo Nordisk, for which the fees go to the institution. He is a DSMB member for a study supported by Roche. The institution of K.F. has received unrestricted research grants from CSL Behring, Bayer and Novo Nordisk and her institution received consultancy fees from Shire, Roche, Novo Nordisk and B.K.M. has received research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, BoehringerIngelheim, BMS and Aspen; and consulting fees from uniQure. P.C. has received grants and/or personal fees from Bayer, Baxalta, Biogen, Bioverativ, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Shire, Spark and Sobi. M.H.C. has received grants from governmental research institutes such as Dutch Research Institute (NWO), ZonMW, Innovation fund, and unrestricted investigator initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/ Baxalta/ Shire, Bayer Schering Pharma, CSL Behring, SobiBiogen, Novo Nordisk, Novartis and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer. All grants, awards and fees go to the institution. R.M. has received travel grants from Shire and Bayer. The UK Enhanced Half-Life registry was funded by a grant from Sobi. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2020 Georg Thieme Verlag KG Stuttgart {\^A}• New York. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = may,
day = "1",
doi = "https://doi.org/10.1055/s-0040-1709522",
language = "English",
volume = "120",
pages = "747--757",
journal = "Thrombosis and haemostasis",
issn = "0340-6245",
publisher = "Schattauer GmbH",
number = "5",
}