1. Passive transfer of polyethylene glycol to liposomal-recombinant human FVIII enhances its efficacy in a murine model for hemophilia A.
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Ramani, Karthik, Purohit, Vivek, Miclea, Razvan, Gaitonde, Puneet, Straubinger, Robert M., and Balu-Iyer, Sathy V.
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BLOOD coagulation disorders , *POLYETHYLENE glycol , *LIPOSOMES , *PHOSPHATIDYLSERINES , *BIOLOGICAL models , *THERAPEUTICS - Abstract
The replacement therapy using recombinant human FVIII (rFVIII) is the first line of therapy for hemophilia A. Approximately 15–30% of the patients develop inhibitory antibodies. Recently, we reported that liposomes composed of phosphatidylserine (PS) could reduce the immunogenicity of rFVIII. However, PS containing liposomal-rFVIII is likely to reduce the systemic exposure and efficacy of FVIII due to rapid uptake of the PS containing liposomes by the reticuloendothelial system (RES). Here, we investigated whether phosphatidylserine (PS) liposomes containing Polyethylene glycol (PEG) (PEGylated), could reduce the immunogenicity of rFVIII and reverse the reduction in systemic exposure of rFVIII. Animals given PEGylated liposomal-rFVIII had lower total and inhibitory anti-rFVIII antibody titers, compared to animals treated with rFVIII alone. The mean stimulation index of CD4+ T-cells from animals given PEGylated liposomal-rFVIII also was lower than for animals that were given rFVIII alone. Pharmacokinetic studies following intravenous dosing indicated that the systemic exposure (area under the activity curve, AUAC0–24h) of PEGylated liposomal-rFVIII was ∼59 IU/mL × h and significantly higher than that of non-PEGylated liposomal-rFVIII (AUAC0–24h ∼ 36 IU/mL × h). Based on these studies, we speculate that PEGylated PS-containing liposomal rFVIII may improve efficacy of rFVIII. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3753–3764, 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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