title: 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.
authors.affiliation: The University of Tennessee Comprehensive Hemophilia Center, Department of Medicine, The University of Tennessee, Memphis, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Deitcher
authors.forename: J
authors.initials: J
authors.lastname: Tuller
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000911:Antibodies, Monoclonal; D003894:Deamino Arginine Vasopressin / Q000627:therapeutic use*; D005169:Factor VIII / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000188:drug therapy* / Q000378:metabolism; D006490:Hemostatics / Q000627:therapeutic use*; D006801:Humans; D016014:Linear Models; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D006490:Hemostatics; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin