Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A.
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.
Division of Hematology and Oncology, University of California at Davis, Sacramento, CA, USA. jspowell@ucdavis.edu
J S
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Powell
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Nugent
J A
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Harrison
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Soni
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Luk
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Stass
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Gorina
D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015926:Complement C3a / Q000032:analysis; D015941:Complement Hemolytic Activity Assay; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005169:Factor VIII / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006474:Hemorrhagic Disorders / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
D008078:Cholesterol, LDL; D008081:Liposomes; C099730:N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D015926:Complement C3a; D005169:Factor VIII; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine