Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration.

 Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability.  Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg  The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5-76), median predose VWF activity was 0.37 IU/mL (range: 0.06-1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04-4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While  A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

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J.M.H. has received an award from CSL Behring, outside the submitted work. F.W.G.L. has received unrestricted research grants from CSL Behring, Takeda, and uniQure, and is a consultant for Takeda, uniQure, and Biomarin of which fees go to the institution. He is a DSMB member for a study sponsored by Roche. OPTI-CLOT member M.J.H.A.K. has received grants from governmental research institutes such as ZonMW, Innovation Fund, as well as institutional grants, and has received unrestricted research grants from Boehringer Ingelheim, Pfizer, Bayer, Daiichi Sankyo, and Sobi, outside the submitted work. She has received speaker's fee from Bayer that goes to the institution. R.A.A.M. has received travel grants from Shire and Bayer. The remaining authors declare no competing financial interests. All unrestricted research grants, awards, educational grants, and consultancy fees have been forwarded to the respective institutions. M.H.C. has received grants from governmental research institutes such as NWO, ZonMW, and Innovation Fund, and institutional grants and unrestricted investigator research grants/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 steering boards of Roche and Bayer. All grants, awards, and fees have gone to the institution.