Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease

Laura H. Bukkems, Jessica M. Heijdra, OPTI-CLOT study group, Nico C.B. de Jager, Hendrika C.A.M. Hazendonk, Karin Fijnvandraat, Karina Meijer, Jeroen C.J. Eikenboom, Britta A.P. Laros-Van Gorkom, Frank W.G. Leebeek, Marjon H. Cnossen, Ron A.A. Mathôt*

*Corresponding author for this work

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Abstract

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).

Original languageEnglish
JournalBlood advances
Volume5
Issue number5
DOIs
Publication statusPublished - 9 Mar 2021

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: J.M.H. has received a grant from CSL Behring outside of the submitted work. K.F. has received unrestricted research grants from CSL Behring, Bayer, and Novo Nordisk, and has received institutional consultancy fees from Shire,

Funding Information:
Acknowledgment L.H.B. was supported by a fund from the Netherlands Organisation for Scientific Research (NWO) in the framework of the Dutch Research Agenda–Research Along Routes by Consortia (NWA-ORC) Call Grant Agreement NWA.1160.18.038.

Funding Information:
Roche, Novo Nordisk, and Bayer. B.A.P.L.-v.G. has received unrestricted educational grants from Baxter and CSL Behring. K.M. has received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, Bristol Myers Squibb (BMS), and Aspen; and consulting fees from uni-Qure. J.C.J.E. received research support from CSL Behring and has been a teacher for Roche, involved with its educational activities. F.W.G.L. received unrestricted research grants from CSL Behring, Shire/Takeda, Sobi, and uniQure; is a consultant for CSL Behring, Shire/Takeda, Biomarin, and uniQure, of which the fees go to the University; received travel support from Sobi; and is a Data and Safety Monitoring Board member of a study sponsored by Roche. M.H.C. has received grants from governmental research institutes such as the Dutch Research Institute (NWO), ZonMW, the Innovation Fund, and NWO-ORC; has received 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, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma; and has served as a member on the steering boards of Roche and Bayer. All grants, awards, and fees go to the institution. R.A.A.M. has received grants from governmental and societal research institutes such as NWO, ZonMW, Kidney Foundation and Innovation Fund; unrestricted investigator research grants from Baxter/Baxalta/Shire/Takeda, Bayer, CSL Behring, Sobi, and CelltrionHC; and has served as advisor for Bayer, CSL Behring, Merck Sharp & Dohme, Baxter/ Baxalta/Shire/Takeda. (All grants and fees were paid to the institution.) The remaining authors declare no competing financial interests.

Publisher Copyright:
© 2021 by The American Society of Hematology

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