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J Pharm Sci. 2015 Feb;104(2):388-95. doi: 10.1002/jps.23963. Epub 2014 Apr 2.

Soy phosphatidylinositol containing nanoparticle prolongs hemostatic activity of B-domain deleted factor VIII in hemophilia A mice.

Author information

1
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York.

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.

KEYWORDS:

B-domain deleted factor VIII; inhibitor development; lipids; next-generation FVIII; pharmacodynamics; pharmacokinetics; phosphatidylinositol nanoparticles; protein delivery; simulations

PMID:
24700333
PMCID:
PMC4183744
DOI:
10.1002/jps.23963
[Indexed for MEDLINE]
Free PMC Article

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