Evaluation of liposomal dose in recombinant factor VIII reconstituted with pegylated liposomes for the treatment of patients with severe haemophilia A.

Abstract

Patients with haemophilia A treated prophylactically require frequent factor VIII (FVIII) infusions for bleed protection. Recombinant sucrose-formulated FVIII (rFVIII-FS) with pegylated liposomes (PEGLip-rFVIII-FS) was previously shown to extend the bleed-free period after prophylactic infusion versus rFVIII-FS using two doses of FVIII with a fixed amount of liposomal diluent. This randomised, subject-blinded, four-way crossover study evaluated the efficacy and safety of PEGLip-rFVIII-FS using various quantities of pegylated liposomes with a fixed FVIII dose. Adults with severe haemophilia A were randomised to one of four treatment arms. Each arm had four treatment segments, with each segment consisting of a prophylactic infusion followed by on-demand infusions. The prophylactic infusions used a fixed dose of 35 IU/kg rFVIII-FS, but varied in the amount of pegylated liposomes used for reconstitution (4.2, 12.6, or 22.1 mg/kg of body weight or water as a control). On-demand infusions all used 35 IU/kg rFVIII-FS. After treatment of spontaneous bleeds and a wash-out, subjects crossed to another treatment segment (i.e. another PEGLip-rFVIII-FS dose or control). Sixteen subjects enrolled in and completed the study. Mean number of bleed-free days after prophylactic infusion increased from 7.8 days for control rFVIII-FS to 8.7, 10.8, and 10.9 days for PEGLip-rFVIII-FS reconstituted in 4.2, 12.6, and 22.1 mg/kg of pegylated liposomes, respectively. The difference in bleed-free days approached but did not achieve statistical significance in this small study population. No drug-related adverse events or inhibitors were reported. This study helps establish the optimal concentration of liposomes in PEGLip-rFVIII-FS to prolong the post-infusion bleed-free period.

• Authors: Jack Spira, Olga P Plyushch, Tatyana A Andreeva, Rosa N Khametova
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 100 Issue 3 Pg. 429-34 (Sep 2008) ISSN: 0340-6245 [Print] Germany
• PMID: 18766258 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Liposomes
• recombinant FVIII, sugar formulated
• Polyethylene Glycols
• Sucrose
• F8 protein, human
• Factor VIII

Topics

• Adult
• Cross-Over Studies
• Factor VIII (chemistry, therapeutic use)
• Hemophilia A (therapy)
• Hemorrhage (prevention & control)
• Humans
• Liposomes (chemistry, therapeutic use)
• Male
• Middle Aged
• Models, Genetic
• Polyethylene Glycols (chemistry)
• Safety
• Sucrose (therapeutic use)
• Time Factors
• Treatment Outcome