Abstract Number: OC 43.2
Meeting: ISTH 2021 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: In patients with Von Willebrand disease (VWD) desmopressin (DDAVP) causes the release of endogenous von Willebrand factor (VWF) from endothelial cells. Current guidelines suggest intravenous (IV) DDAVP given as 0.3 mcg/kg, with a maximum dose of 20-30 mcg.
Aims: To describe the relationship between DDAVP dose, DDAVP plasma concertation and VWF:Activity (VWF:Act) and to evaluate whether a capped dose is rational.
Methods: A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed using data from 54 patients (median age 25, range[8 – 70], median bodyweight 72, range[35 – 123], 17 type 1, 6 type 2 and 30 low VWF). Patients received an IV DDAVP dose of 0.3 mcg/kg. Four samples were taken to assess DDAVP plasma concentration and VWF:Act. With the developed PK-PD model Monte Carlo simulations were performed.
Results: Time profiles of plasma concentrations of DDAVP were best described by an one-compartment model. Females had a 27% higher volume of distribution than males. In the PD analysis, a lag between the rise in DDAVPO concentration and the VWF:Act was described using a turn-over model (figure 1).
Schematic overview of the developed population pharmacokinetic-pharmacodynamic model.
The relationship between DDAVP concentration and the rise in VWF:Act was best described with a Emax PD model. Estimated EC50 was 0.148 ng/mL and the maximum effect of DDAVP on the VWF:Act was estimated at 0.5 ng/mL.. Simulations on basis of the developed model demonstrated that >90% of VWD patients with a baseline of 0.2 IU/mL attain VWF:Act >0.5 IU/mL 4h after administration of 0.3 mcg/kg DDAVP. Doses higher than 30 mcg did not improve the VWF:Act response (figure 2).
Time-course simulations of desmopressin (DDAVP) and VWF:Act in 1000 females with a body weight of 130kg and 30 mcg DDAVP. The red and blue solid lines depict, respectively the median DDAVP and VWF:Act concentrations. The shaded areas depict the 80% prediction interval.
Conclusions: An integrated PKPD model was developed describing the dose, concentration, response relationship of DDAVP. The developed model provided a pharmacological basis for the present guidelines.
To cite this abstract in AMA style:
Cloesmeijer M, Heijdra J, de Jager N, Cnossen M, Mathôt R. Quantifying the Concentration-effect Relation of Desmopressin on the von Willebrand Factor Activity in Patients with von Willebrand Disease [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/quantifying-the-concentration-effect-relation-of-desmopressin-on-the-von-willebrand-factor-activity-in-patients-with-von-willebrand-disease/. Accessed September 24, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/quantifying-the-concentration-effect-relation-of-desmopressin-on-the-von-willebrand-factor-activity-in-patients-with-von-willebrand-disease/