Subscribe to RSS
DOI: 10.1160/TH08-03-0133
Evaluation of liposomal dose in recombinant factor VIII reconstituted with pegylated liposomes for the treatment of patients with severe haemophilia A
Publication History
Received
04 March 2008
Accepted after minor revision
27 June 2008
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200803/lookinside/thumbnails/10-1160-th08-03-0133-1.jpg)
Summary
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.
-
References
- 1 Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994; 236: 391-399.
- 2 Manco-Johnson MJ, Riske B, Kasper CK. Advances in care of children with hemophilia. Semin Thromb Hemost 2003; 29: 585-594.
- 3 Manco-Johnson MJ. Update on treatment regimens: prophylaxis versus on-demand therapy. Semin Hematol 2003; 40: 3-9.
- 4 Nilsson IM, Hedner U, Ahlberg A. Haemophilia prophylaxis in Sweden. Acta Paediatr Scand 1976; 65: 129-135.
- 5 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-544.
- 6 Nilsson IM, Berntorp E, Lofqvist T. et al. Twentyfive years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
- 7 National Hemophilia Foundation. MASAC Recommendations Concerning Prophylaxis (Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). 2006 Report No.: 170.
- 8 World Health Organization. Report of Joint WHO/ WFH Meeting on the Control of Haemophilia: Delivery of Treatment for Haemophilia. 2002
- 9 Berntorp E, Bjorkman S. The pharmacokinetics of clotting factor therapy. Haemophilia 2003; 09: 353-359.
- 10 Bjorkman S. Prophylactic dosing of factor VIII and factor IX from a clinical pharmacokinetic perspective. Haemophilia 2003; 09 (Suppl. 01) 101-108.
- 11 Bjorkman S, Berntorp E. Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet 2001; 40: 815-832.
- 12 Bjorkman S, Carlsson M, Berntorp E. et al. Pharmacokinetics of factor VIII in humans. Obtaining clinically relevant data from comparative studies. Clin Pharmacokinet 1992; 22: 385-395.
- 13 Carlsson M, Berntorp E, Bjorkman S. et al. Pharmacokinetic dosing in prophylactic treatment of hemophilia A. Eur J Haematol 1993; 51: 247-252.
- 14 Bhadra D, Bhadra S, Jain P. et al. Pegnology: a review of PEG-ylated systems. Pharmazie 2002; 57: 5-29.
- 15 Oussoren C, Storm G, Crommelin DJA. et al. Liposomes for sustained drug release. In: Sustained-release injectable products. Interpharm Press, Engelwood; Colorado, USA: 2000: 137-180.
- 16 Park JW, Benz CC, Martin FJ. Future directions of liposome- and immunoliposome-based cancer therapeutics. Semin Oncol 2004; 31: 196-205.
- 17 Powell JS, Nugent DJ, Harrison JA. et al. Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A. J Thromb Haemost 2008; 06: 277-283.
- 18 Baru M, Carmel-Goren L, Barenholz Y. et al. Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy. Thromb Haemost 2005; 93: 1061-1068.
- 19 Spira J, Plyushch OP, Andreeva TA. et al. Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes. Blood 2006; 108: 3668-3673.
- 20 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
- 21 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia 2001; 07: 392-396.
- 22 Ljung R. The risk associated with indwelling catheters in children with haemophilia. Br J Haematol 2007; 138: 580-586.