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

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Powell, J. S.; Nugent, D. J.; Harrison, J. A.; Soni, A.; Luk, A.; Stass, H.; Gorina, E.

BACKGROUND: BAY 79-4980 is a sucrose-formulated recombinant factor VIII (rFVIII-FS) combined with pegylated liposomes to prolong activity. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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