title: Recombinant fusion protein linking factor VIIa with albumin (rVIIa-FP): Tissue distribution in rats.
abstract: BACKGROUND
  A novel fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) is currently undergoing clinical investigations.
  
  
  OBJECTIVE
  This study was conducted to examine the biodistribution of rVIIa-FP in comparison to recombinant factor VIIa (rFVIIa).
  
  
  METHODS
  [(3)H]-rVIIa-FP (10mgkg(-1)) or [(3)H]-rFVIIa (1.6mgkg(-1)) were administered intravenously to rats, followed by quantitative whole-body and knee joint autoradiography for 24 ([(3)H]-rFVIIa) or 240 ([(3)H]-rVIIa-FP) hours post-dose. Pharmacokinetic and excretion balance analyses were performed.
  
  
  RESULTS
  In contrast to [(3)H]-albumin, the tissue distributions of [(3)H]-rVIIa-FP and [(3)H]-rFVIIa were similar. Within the knee, both were rapidly present within synovial and mineralized regions. Importantly, rVIIa-FP- and albumin-derived radioactivity were detectable up to 72-120hours, whereas [(3)H]-rFVIIa signals were already close to detection limits at 24hours. The longest rVIIa-FP retention times were observed in bone marrow and endosteum, in which the retention times were up to 5 times longer for rVIIa-FP compared with rFVIIa. Up to 8hours post-dose, 100% of radioactivity was assigned to unchanged [(3)H]-rVIIa-FP. Elimination of both proteins occurred primarily via the urine.
  
  
  CONCLUSIONS
  The data suggest that the FVIIa moiety is directing rVIIa-FP's tissue distribution while the albumin moiety is responsible for the prolonged tissue retention. Importantly, rVIIa-FP is highly concentrated and retained over a long period in the growth plate of the knee joint-a vulnerable site in haemophilia patients. Overall, these improved tissue distribution characteristics of rVIIa-FP may enhance compliance and allow a more convenient dosing frequency.
authors: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany. Electronic address: eva.herzog@cslbehring.com.
authors: Eva
authors: E
authors: Herzog
authors: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors: Stephen
authors: S
authors: Harris
authors: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors: Andrew
authors: A
authors: McEwen
authors: Quotient Bioresearch Metabolic Chemistry, Rushden, UK.
authors: Claire
authors: C
authors: Henson
authors: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors: Ingo
authors: I
authors: Pragst
authors: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors: Gerhard
authors: G
authors: Dickneite
authors: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors: Stefan
authors: S
authors: Schulte
authors: CSL Behring GmbH, Preclinical Research and Development, Marburg, Germany.
authors: Sabine
authors: S
authors: Zollner
mesh_terms: D000818:Animals; D015942:Factor VIIa / Q000235:genetics / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000235:genetics / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin; C103587:recombinant FVIIa; D015942:Factor VIIa
keywords: Albumin fusion; Blood coagulation disorders; Factor VIIa; Haemophilia; Recombinant proteins; Tissue distribution; rVIIa-FP