Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

• Published in: Journal of pharmaceutical sciences Vol. 105; no. 8; pp. 2459 - 2464
• Main Authors: Shetty, Krithika A., Merricks, Elizabeth P., Raymer, Robin, Rigsbee, Natalie, Nichols, Timothy C., Balu-Iyer, Sathy V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016
• Subjects: Animals; Dogs; Drug Carriers - chemistry; Drug Compounding; Drug Stability; Factor VIII - administration & dosage; Factor VIII - pharmacokinetics; Factor VIII - therapeutic use; Female; Glycine max - chemistry; Hemophilia A - blood; Hemophilia A - drug therapy; Hemostatics - administration & dosage; Hemostatics - blood; Hemostatics - therapeutic use; Injections, Intravenous; Models, Biological; nanoparticles; Nanoparticles - chemistry; pharmacodynamics; pharmacokinetics; Phosphatidylinositols - chemistry; phospholipids; protein delivery; Recombinant Proteins; pharmacokinetics; nanoparticles; phospholipids; protein delivery; pharmacodynamics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2016.05.023

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.