PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Journal Title: The AAPS Journal - Year 2012, Vol 14, Issue 1

Abstract

Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease. Previously, we used phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII–PI formulation resulting from the addition of polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated lipid into the FVIII–PI complex. PEGylated FVIII–PI (FVIII–PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in hemophilia A mice. Following intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII–PI, but exposure determined by area under the curve was reduced. The formation of inhibitory antibodies after subcutaneous immunization with FVIII–PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following intravenous administration. Passive transfer of PEG onto the FVIII–PI complex does not provide any therapeutic benefit.

Authors and Affiliations

Aaron Peng, Matthew P. Kosloski, Genki Nakamura, Hong Ding, Sathy V. Balu-Iyer

Keywords

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  • EP ID EP681185
  • DOI  10.1208/s12248-011-9309-2
  • Views 87
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How To Cite

Aaron Peng, Matthew P. Kosloski, Genki Nakamura, Hong Ding, Sathy V. Balu-Iyer (2012). PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice. The AAPS Journal, 14(1), -. https://www.europub.co.uk/articles/-A-681185