Von Willebrand Disease (VWD) - A Disease with Dual Factor Deficiencies- Discrepant FVIII:C Pharmacokinetic (PK) Characteristics in a Head to Head Trial of Two VWF/FVIII Concentrates.

Introduction: The PK profile of VWF/FVIII concentrate is very important in the treatment of individuals with VWD since this coagulopathy is a combined deficiency of qualitative and/or quantitative VWF functions specifically and of FVIII activity indirectly. A prospective randomized, crossover study was performed to investigate the PK properties of two VWF/FVIII concentrates (Wilate® and Humate-P®) in subjects with inherited VWD. This is the first head-to-head PK study performed within the same subject, comparing two plasma derived concentrates, one a new high purity VWF/FVIII product (Wilate) and an existing first generation intermediate purity concentrate (Humate-P).

Methods: This prospective, randomized, controlled, open-labeled, 2-arm crossover, multi-center study included subjects with inherited and defined VWD, who underwent PK assessments after random allocation in Period 1 to a single 40 IU VWF:RCo /kg bolus dose of either Wilate or with Humate-P. After a washout period of at least 7 days, subjects received the other study VWD replacement concentrate for Period 2. During both study periods, plasma samples were tested at multiple time points for coagulation factor activities. The objective of the study was to evaluate the PK profiles of both, including the in-vivo terminal half-life (t1/2) of FVIII:C, VWF:RCo, VWF:Ag, and VWF:CB.

Results: A total of 22 subjects with inherited VWD (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 the study. The VWF PK profiles for VWF after Wilate or Humate-P were similar with no appreciable difference in the mean t1/2 for VWF activities in Type 3 and Type 1 subjects (10 hrs for Humate-P and 12.6 hrs for Wilate using the VWF:RCo assay). For VWD Type 2 subjects the mean t1/2 was longer, but with no consistent differences between the concentrates. There were no significant differences in recovery, and consequently Cmax and AUC between Wilate and Humate-P. In patients receiving Wilate, there were almost parallel decay curves and t1/2 between VWF (RCo-12.6hr) and FVIII (FVIIIC -13hr) activity. In the analysis of FVIII:C PK profiles, Humate- P showed an unusually sustained FVIII:C decay curve plateau, which may represent the net combined effects of decreasing exogenous and increasing endogenous FVIII activities in the patient and the increased FVIII:C binding capacity of the excessive quantity of non-functional VWF:Ag present in this product. There was a significant discrepancy in the mean t1/2 for FVIII:C measured in VWD Type 3 subjects (35.7 hrs for Humate-P and 13 hrs for Wilate), using either one stage or chromogenic FVIII:C assays.

Conclusions: This study confirms the similarity of the VWF PK properties of Wilate and Humate-P. However, this was not the case for FVIII activity, which revealed a significantly prolonged t1/2 versus the t1/2 of VWF:RCo for Humate-P measured in type 3 VWD patients after infusion. In contrast, following infusion of Wilate there was the initial expected FVIII:C peak followed by a parallel decay curves for both VWF:RCo and FVIII:C activities. This favorable PK profile for the new high purity VWF/FVIII concentrate, Wilate, should facilitate the dosing and laboratory monitoring of VWF replacement in VWD and should improve safety and efficacy by avoiding over or under dosing of each of the two critical coagulation parameters, especially in the situation of repeated dosing of the concentrates.