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  • Title: Soy phosphatidylinositol containing nanoparticle prolongs hemostatic activity of B-domain deleted factor VIII in hemophilia A mice.
    Author: Shetty KA, Kosloski MP, Mager DE, Balu-Iyer SV.
    Journal: J Pharm Sci; 2015 Feb; 104(2):388-95. PubMed ID: 24700333.
    Abstract:
    Factor VIII (FVIII) replacement therapy in hemophilia A (HA) is complicated by a short half-life and high incidence of inhibitory antibody response against the protein. Phosphatidylinositol (PI) containing lipidic nanoparticles have previously been shown to reduce the immunogenicity and prolong the half-life of full length FVIII. It has not been established whether this prolongation in half-life improves hemostatic efficacy and whether this approach could be extended to the B-domain deleted form of FVIII (BDD FVIII). In the current study, we evaluated the pharmacokinetics (PK), hemostatic efficacy, and immunogenicity of BDD FVIII associated with PI nanoparticles (PI-BDD FVIII) in HA mice. Comparative human PK was predicted using an "informed scaling" approach. PI-BDD FVIII showed an approximate 1.5-fold increase in terminal half-life compared with free BDD FVIII following i.v. bolus doses of 40 IU/kg. PI-BDD FVIII-treated animals retained hemostatic efficacy longer than the free FVIII-treated group in a tail vein transection model of hemostasis. PI association reduced the development of inhibitory and binding antibodies against BDD FVIII after a series of i.v. injections. The combined improvements in circulating half-life and hemostatic efficacy could significantly prolong the time above clinically established therapeutic thresholds of prophylactic FVIII replacement therapy in humans.
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