title: Enhancement of factor VIIa haemostatic efficacy by formulation with PEGylated liposomes.
abstract: Recombinant activated factor VII (rFVIIa) is an effective treatment of the haemophilia patient with inhibitors and acquired haemophilia. However, on account of its relatively short half-life (HL), achieving therapeutic efficacy with FVIIa requires repeated injections. The development of a long-acting FVIIa product would therefore be beneficial. The formulation of factor VIII with PEGylated liposomes (PEGLip) was previously shown to extend the bleeding-free period in haemophilia patients. We report here an enhancement of haemostatic efficacy by similarly formulating FVIIa with PEGLip. Surface plasmon resonance analysis indicated that FVIIa binds non-covalently but with high affinity and specificity to PEGLip. A one-stage clotting assay demonstrated that formulation of FVIIa with PEGLip does not affect FVIIa activity and stability. A pharmacokinetic study in rats demonstrated that PEGLip formulation of FVIIa extends circulation time and results in higher FVIIa levels several hours after injection. Thromboelastography experiments indicated that PEGLip-FVIIa induces faster clot formation and higher clot stability than standard formulated FVIIa. These results suggest that formulation of FVIIa with PEGLip may lead to a safe and effective long-acting FVIIa that improves the care of haemophilic patients with inhibitors and acquired haemophilia.
authors.affiliation: Omri Laboratories Ltd, Rehovot, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Yatuv
authors.forename: I
authors.initials: I
authors.lastname: Dayan
authors.forename: L
authors.initials: L
authors.lastname: Carmel-Goren
authors.forename: M
authors.initials: M
authors.lastname: Robinson
authors.forename: I
authors.initials: I
authors.lastname: Aviv
authors.forename: M
authors.initials: M
authors.lastname: Goldenberg-Furmanov
authors.forename: M
authors.initials: M
authors.lastname: Baru
mesh_terms: D000818:Animals; D003029:Coagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008081:Liposomes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013916:Thrombelastography / Q000706:statistics & numerical data
chemical_list: D003029:Coagulants; D008081:Liposomes; D015942:Factor VIIa