Soy phosphatidylinositol containing nanoparticle prolongs hemostatic activity of B-domain deleted factor VIII in hemophilia A mice.
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.
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York.
Krithika A
KA
Shetty
Matthew P
MP
Kosloski
Donald E
DE
Mager
Sathy V
SV
Balu-Iyer
D000818:Animals; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy*; D006490:Hemostatics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D010716:Phosphatidylinositols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013025:Glycine max / Q000737:chemistry*
C451034:B-domain-deleted factor VIII; D006490:Hemostatics; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D005169:Factor VIII
B-domain deleted factor VIII; inhibitor development; lipids; next-generation FVIII; pharmacodynamics; pharmacokinetics; phosphatidylinositol nanoparticles; protein delivery; simulations