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

Bukkems, Laura H., Heijdra, Jessica M., de Jager, Nico C. B., Hazendonk, Hendrika C. A. M., Fijnvandraat, Karin, Meijer, Karina, Eikenboom, Jeroen C. J., Laros-van Gorkom, Britta A. P., Leebeek, Frank W. G., Cnossen, Marjon H., Mathôt, Ron A. A. and Collins, P. W. ORCID: https://orcid.org/0000-0002-6410-1324 2021. Population pharmacokinetics of the von Willebrand factor–factor VIII interaction in patients with von Willebrand disease. Blood Advances 5 (5) , pp. 1513-1522. 10.1182/bloodadvances.2020003891

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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).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Business Relationships, Accountability, Sustainability and Society (BRASS)
Additional Information:	P. W. Collins is a member of the OPTI-CLOT Study Group
Publisher:	American Society of Hematology
ISSN:	2473-9529
Date of First Compliant Deposit:	9 February 2022
Date of Acceptance:	21 January 2021
Last Modified:	22 May 2023 23:59
URI:	https://orca.cardiff.ac.uk/id/eprint/147348

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