title: Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs.
abstract: Soy phosphatidylinositol (PI)-containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain-deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII-treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII-treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214.
authors.forename: Krithika A
authors.initials: KA
authors.lastname: Shetty
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516.
authors.forename: Robin
authors.initials: R
authors.lastname: Raymer
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516.
authors.forename: Natalie
authors.initials: N
authors.lastname: Rigsbee
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214. Electronic address: svb@buffalo.edu.
authors.forename: Sathy V
authors.initials: SV
authors.lastname: Balu-Iyer
mesh_terms: D000818:Animals; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006490:Hemostatics / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D007275:Injections, Intravenous; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010716:Phosphatidylinositols / Q000737:chemistry*; D011994:Recombinant Proteins; D013025:Glycine max / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D006490:Hemostatics; D010716:Phosphatidylinositols; D011994:Recombinant Proteins; C427184:recombinant factor VIII SQ; D005169:Factor VIII
keywords: nanoparticles; pharmacodynamics; pharmacokinetics; phospholipids; protein delivery