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

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels ma y: enhance the infused FVIII concentrate intravascular survival and efficac y in severe haemophiliacs. To assess whether the kinetic characteristics an d recovery of high purity, plasma-derived (Monoclate-P(R), Centeon) and rec ombinant (BioClate(TM), Centeon) FVIII concentrates are enhanced by increas ed plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h afte r the,intranasal delivery of 300 mu g of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate(TM), Centeon) in 10 adult severe haemoph iliacs. FVIII activity-was determined using a one-stage Me clotting assay-o n cryopreserved plasma specimens obtained at baseline and at 14 distinct ti me points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor,a ctivity: (RCoFA) and vWf antigen levels were assayed at baseline and 2 h af ter Stimate(TM) FVIII kinetic parameters were calculated using standard, no ncompartmental 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 Stima te(TM) were significant (P < 0.01 and P < 0.0001, respectively). The mean i ncreases 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 ar m and the FVIII plus Stimate(TM) 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(R) cohort, but not in the Bioclate(TM) group, These-data suggest that even modest pharmacologically induced incre ases in plasma vWf can favourably affect the kinetics of high-purity, plasm a-derived FVIII concentrates in severe haemophiliacs.