Quantification of the relationship between desmopressin concentration and Von Willebrand factor in Von Willebrand...

Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified.

To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients.

Forty-seven VWD patients (median age 25 years, IQR: 19-37; median body weight 71 kg, IQR: 59-86) received an IV desmopressin dose of .3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen.

A one-compartment PK model best described the time profile of the desmopressin concentrations. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typically, VWF:Act increased 452% with an EC50 of .174 ng/ml. Simulations demonstrated that after .3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg.

The relationship between desmopressin and VWF:Act was quantified in a PK-PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of .3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response.