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

J Thromb Haemost. 2008 Feb;6(2):277-83. doi: 10.1111/j.1538-7836.2008.02856.x. Epub 2007 Nov 26.

Abstract

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.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Cholesterol, LDL
  • Liposomes
  • N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • Recombinant Proteins
  • Polyethylene Glycols
  • Complement C3a
  • Factor VIII
  • Cholesterol
  • 1-palmitoyl-2-oleoylphosphatidylcholine