Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A

• Published in: Journal of thrombosis and haemostasis Vol. 6; no. 2; pp. 277 - 283
• Main Authors: Powell, J S, Nugent, D J, Harrison, J A, Soni, A, Luk, A, Stass, H, Gorina, E
• Format: Journal Article
• Language: English
• Published: England 01.02.2008
• Subjects: Adolescent; Adult; Biological Availability; Cholesterol - blood; Cholesterol, LDL - blood; Complement C3a - analysis; Complement Hemolytic Activity Assay; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Factor VIII - administration & dosage; Factor VIII - adverse effects; Factor VIII - pharmacokinetics; Factor VIII - therapeutic use; Half-Life; Hemophilia A - blood; Hemophilia A - drug therapy; Hemorrhagic Disorders - chemically induced; Humans; Infusions, Intravenous; Liposomes; Male; Metabolic Clearance Rate; Middle Aged; Phosphatidylcholines - administration & dosage; Phosphatidylcholines - pharmacokinetics; Phosphatidylethanolamines - administration & dosage; Phosphatidylethanolamines - pharmacokinetics; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use
• ISSN: 1538-7933; 1538-7836
• DOI: 10.1111/j.1538-7836.2007.02856.x

BAY 79-4980 is a sucrose-formulated recombinant factor VIII (rFVIII-FS) combined with pegylated liposomes to prolong activity. To investigate the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of a single administration of BAY 79-4980 compared with standard rFVIII-FS in patients with severe hemophilia A. This randomized, double-blind study consisted of two crossover substudies comparing two doses of liposomal rFVIII-FS with standard rFVIII-FS. Males (12-60 years) with severe hemophilia A received a single infusion of standard rFVIII-FS (35 IU kg(-1)) followed by a single infusion of BAY 79-4980 (13 or 22 mg kg(-1) pegylated liposomes) or vice versa, with 12 observation days and a 2-day washout period between treatments. Twenty-six subjects were enrolled at two centers. No serious adverse events were reported. Transient increases in complement C3a, but not CH50, were seen in subjects receiving both the low- and high-liposome-dose BAY 79-4980. Mild transient elevations of total and low-density lipoprotein cholesterol were observed. There were no clinically significant differences in clotting or laboratory parameters or in pharmacokinetic behavior between BAY 79-4980 and standard rFVIII-FS. The number of subjects with spontaneous bleeds on days 1-14 postinfusion was low, and group comparisons were inconclusive. Single-dose administration of BAY 79-4980 is well tolerated in patients with severe hemophilia A. Plasma pharmacokinetics of FVIII cannot explain the extended protection from bleeding observed previously with BAY 79-4980. Further studies of efficacy and long-term safety of chronic administration are planned.