Von Willebrand factor

Von Willebrand factor solution for injection behaves in the same way as endogenous von Willebrand factor.

Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency at two levels:

• VWF re-establishes platelet adhesion to the vascular subendothelium at the site of vascular damage (as it binds both to the vascular subendothelium and to the platelet membrane) providing primary haemostasis as shown by the shortening of the bleeding time. This effect is known to depend to a large extent on the level of multimerisation of the active substance.
• Von Willebrand factor produces delayed correction of the associated factor VIII deficiency. Administered intravenously, von Willebrand factor binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation. Because of this, administration of pure von Willebrand factor (VWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion. Administration of a FVIII:C containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

A pharmacokinetic study with Von Willebrand factor was carried out on 8 patients with type 3 von Willebrand disease. It demonstrated that for VWF:RCo:

• The mean AUC_0-∞ is 3444 IU.h/dl after single dose of 100 IU/kg Von Willebrand factor solution,
• The plasma peak is reached between 30 minutes and 1 hour after injection,
• The mean recovery is 2.1 [IU/dl]/[IU/kg] of the injected preparation,
• The half-life is between 8 and 14 hours, with a mean value of 12 hours,
• The mean clearance is 3.0 ml/h/kg.

Normalisation of FVIII level is progressive, varies and usually requires between 6 and 12 hours. This effect is sustained for 2 to 3 days.

The increase in FVIII level is progressive and returns to normal after 6 to 12 hours. The FVIII level increases by a mean of 6% (IU/dl) per hour. Thus, even in patients with an initial FVIII:C level less than 5% (IU/dl), the FVIII:C level increases to around 40% (IU/dl) 6 hours after the injection, and this level is maintained over 24 hours.

Based on data obtained from several preclinical studies using animal models, there is no evidence for other toxic effect of Von Willebrand factor than those related to the immunogenicity of human proteins in laboratory animals. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models.

The preclinical safety data do not suggest that Von Willebrand factor has any mutagenic potential.