Comparison of Pharmacokinetic Properties of Two VWF/FVIII Concentrates In Subjects with Inherited Von Willebrand Disease (VWD)- Results of a Prospective, Randomized, Crossover Study.

Understanding pharmacokinetic (PK) profiles of von Willebrand Factor (VWF)/Factor VIII (FVIII) concentrates is important in the treatment of VWD. This prospective, randomized, open-label, crossover trial investigated the PK characteristics of two plasma-derived (pd) VWF/FVIII concentrates (Wilate^® [high-purity (HP)] and Humate-P^® [intermediate-purity (IP)]) in subjects with inherited VWD.

After a wash-out period, twenty-two subjects (Type 1, n=6; Type 2, n=9 [6 Type 2A, 1 Type 2B, and 2 Type 2M]; and Type 3, n=7) were randomized in a prospective, controlled, open-labeled, 2-arm crossover, to receive 40 IU VWF:RCo/kg of Wilate^® or Humate-P^® followed by another washout period and administration of the other study drug. Blood samples were taken at multiple time-points over 72hrs for PK evaluations.

A non compartmental statistical model was used to analyze the data. The mean VWF:RCo half-life for Type-3 subjects was similar for the HP product (9.1 hours [±2.6]) and IP product (10.2 hours [±2.1]. For all study participants there were no significant differences in incremental in-vivo recoveries (≂f2.0 IU VWF:RCo/dL per IU/kg), or in clearance. Bioequivalence between the two products was shown for the main VWF PK parameters. The decay-curves for VWF:RCo and FVIII:C in the HP product showed a parallel decay, while the IP product did not and showed an unusually sustained FVIII plateau over the initial decay time period. The data showed an almost a 2 fold decrease in clearance between the two products. The chromogenic FVIII:C terminal half live for the two products were similar (16.1hrs [SD=3.1] HP product and 20.5 hrs [SD=7.6] IP product), although the average half lives were quite different (13 hrs [SD=4.1] HP product and 37.7 hrs [SD=6.4] IP product). This was in spite of the much higher initial FVIII concentration profile of the 1:1 VWF/FVIII HP product. The 2.4:1 VWF/FVIII IP product showed an expected lower mean FVIII:C peak value due to the excess of VWF:RCo activity in the product that was based on VWF:RCo unit dosing, but similar both products had a similar dose adjusted IVR.

This study confirms the similarity of the VWF PK properties of the two licensed VWF products. However, the analysis of FVIII activity, in the two products revealed some differences in their PK profiles. With the similar PK-properties for VWF:RCo and FVIII:C, Wilate showed a more parallel course for the two active components. A more predictable PK profile for both VWF and FVIII in a product may facilitate both more accurate dosing and laboratory monitoring of VWF replacement in VWD treatment. A parallel PK profile together with an equal ratio for FVIII and VWF activities may help avoid over or under dosing of either of the two critical coagulation parameters.

Kessler:Grifols S.A.: Research Funding. Schwartz:Octapharma: Employment.