title: Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats.
abstract: BACKGROUND
  The recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is undergoing clinical trials for prophylaxis and on-demand treatment of haemophilia B patients. The aim of this study was to investigate the pharmacokinetics, whole-body and knee joint distribution of rIX-FP following intravenous administration to rats, compared with a marketed, non-fused rFIX and recombinant human albumin.
  
  
  METHODS
  [(3)H]-rIX-FP, [(3)H]-rFIX or [(3)H]-albumin were administered to rats followed by quantitative whole-body autoradiography over 24 or 240 hours, and the tissue distribution as well as elimination of radioactivity were measured.
  
  
  RESULTS
  Elimination of all radioactivity derived from the three proteins was shown to occur primarily via the urine. The tissue distribution of [(3)H]-rIX-FP and [(3)H]-rFIX (but not of [(3)H]-albumin) was comparable, both penetrating predominantly into bone, and well-perfused tissues, suggesting that the rIX moiety determines the distribution pattern of rIX-FP, while the albumin moity is responsible for the prolonged plasma and tissue retention. Detailed knee-joint analysis indicated rapid presence of [(3)H]-rIX-FP and [(3)H]-rFIX in synovial and mineralised bone tissue, mostly localised to the zone of calcified cartilage. Longest retention times were observed in the bone marrow and the endosteum of long bones. Intriguingly, [(3)H]-rIX-FP- and [(3)H]-albumin-derived radioactive signals were detectable up to 240 hours, while [(3)H]-rFIX-derived radioactivity rapidly declined after 1hour post-dosing correlating to the extended plasma half-life of [(3)H]-rIX-FP.
  
  
  CONCLUSIONS
  The prolonged plasma and tissue retention of rIX-FP achieved by albumin fusion may allow a reduction in dosing frequency leading to increased therapeutic compliance and convenience.
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany. Electronic address: eva.herzog@cslbehring.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.affiliation: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Harris
authors.affiliation: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Henson
authors.affiliation: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McEwen
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schenk
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041 Marburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zollner
mesh_terms: D000418:Albumins / Q000493:pharmacokinetics*; D000818:Animals; D005164:Factor IX / Q000493:pharmacokinetics*; D006801:Humans; D007719:Knee Joint / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000418:Albumins; D011993:Recombinant Fusion Proteins; D005164:Factor IX
keywords: Albumin fusion; Biodistribution; Coagulation factor IX; Pharmacokinetics; Recombinant factor IX