Intranasal DDAVP induced increases in plasma von Willebrand factor alter the pharmacokinetics of high‐purity factor VIII concentrates in severe haemophilia A patients

Abstract

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels may enhance the infused FVIII concentrate intravascular survival and efficacy in severe haemophiliacs. To assess whether the kinetic characteristics and recovery of high purity, plasma-derived (Monoclate-P, Centeon) and recombinant (Bioclate , Centeon) FVIII concentrates are enhanced by increased plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h after the intranasal delivery of 300 microg of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate, Centeon) in 10 adult severe haemophiliacs. FVIII activity was determined using a one-stage clotting assay on cryopreserved plasma specimens obtained at baseline and at 14 distinct time points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor activity (RCoFA) and vWf antigen levels were assayed at baseline and 2 h after Stimate. FVIII kinetic parameters were calculated using standard, noncompartmental kinetic methods. Statistical analysis was performed using a paired t-test with 95% confidence limits. The mean rises in RCoFA (0.65+/-0.44 IU mL(-1)) and vWf antigen (0.19+/-0.07 IU mL-1) induced by Stimate were significant (P<0.01 and P<0.0001, respectively). The mean increases in the volume of distribution at steady state (Vss) (13.2+/-9.3 dL) and mean residence time (MRT) (4.4+/-3.9 h) between the FVIII-only arm and the FVIII plus Stimate arm were highly significant (P = 0.0015 and P = 0. 0059, respectively). The mean differences in recovery, area under the curve (AUC), half-life, and clearance (Cl) were not significantly altered. Subgroup analysis revealed statistically significant increases in Vss and MRT (P = 0.025 and P = 0.012, respectively) following the administration of intranasal DDAVP in the Monoclate-P cohort, but not in the Bioclate group. These data suggest that even modest pharmacologically induced increases in plasma vWf can favourably affect the kinetics of high-purity, plasma-derived FVIII concentrates in severe haemophiliacs.

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

“…39 In addition, Deitcher et al have shown that volume of distribution increases after desmopressin administration, which, of course, results in an overall increase in VWF levels. 40 Moreover, we believe that VWF may play a crucial role in the perioperative setting with regard to FVIII PK parameters, as previous studies have demonstrated a clear association between VWF plasma concentrations and FVIII halflife. 41,42 This is not surprising, as VWF protects FVIII against proteolytic degradation by expression of ABH antigens on N-linked glycans and the uptake of the copper-binding protein ceruloplasmin.…”

Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A

“…by inhibiting the binding of activated PC to FVIII [30]. Interestingly, in previous studies it has not been possible to prolong FVIII halflife in patients with haemophilia A by the infusion of desmopressin, which leads to an increase of plasma VWF [28,31]. It is important to mention that also the half-life of the novel FVIII concentrates with prolonged half-life is associated with VWF levels [32].…”

Biological mechanisms underlying inter‐individual variation in factor VIII clearance in haemophilia

“…Similarly, human studies have shown that DDAVP administration can significantly increase endogenous plasma VWF:Ag levels in PWH. However, DDAVP pre‐treatment 2 hours prior to infusion of FVIII had no significant effect on FVIII clearance 49 …”