title: Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect.
abstract: BACKGROUND
  Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study.
  
  
  METHODS
  Ten factor VII deficient patients were treated with either recombinant activated (20 μg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points.
  
  
  RESULTS
  Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII.
  
  
  CONCLUSIONS
  Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products.
authors.affiliation: Laboratory of Haematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Natascha C J
authors.initials: NC
authors.lastname: Mathijssen
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Pal Andre
authors.initials: PA
authors.lastname: Holme
authors.forename: Marian G J
authors.initials: MG
authors.lastname: van Kraaij
authors.forename: Britta A P
authors.initials: BA
authors.lastname: Laros-van Gorkom
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Waander L
authors.initials: WL
authors.lastname: van Heerde
mesh_terms: D000328:Adult; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D005168:Factor VII Deficiency / Q000097:blood* / Q000188:drug therapy*; D015942:Factor VIIa / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006487:Hemostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D015942:Factor VIIa
keywords: AUC; Area Under the Curve; Cl; Cmax; Coagulation; FVII; Factor VII; Half-life; Hb; Hemoglobin; Hemostasis; IVR; Incremental In Vivo Recovery; MRT; Mean Residence Time; NCA; Non-Compartmental Analysis; OCA; One-Compartmental Analysis; Peak plasma concentration of a drug after administration; Pharmacokinetics; Plasma-derived factor VII; Recombinant activated factor VII; Total body clearance; T½; Volume of distribution at steady-state; Vss; pdFVII; rFVIIa