title: Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding.
abstract: BACKGROUND
  Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown.
  
  
  METHODS
  In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 microg x kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 microg x kg-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)).
  
  
  RESULTS
  Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml x kg-1 x h-1; central volume of distribution 89 (32% CV) ml x kg-1; inter-compartmental clearance 24 ml x kg-1 x h-1; and peripheral compartment volume 31 ml x kg-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U x ml-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters.
  
  
  CONCLUSIONS
  A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.
authors.affiliation: Department of Biomodelling, Novo Nordisk A/S, Maaloev, Denmark. tkt@novonordisk.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Klitgaard
authors.forename: Rene
authors.initials: R
authors.lastname: Tabanera y Palacios
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Boffard
authors.forename: Philip T C
authors.initials: PT
authors.lastname: Iau
authors.forename: Brian
authors.initials: B
authors.lastname: Warren
authors.forename: Sandro
authors.initials: S
authors.lastname: Rizoli
authors.forename: Rolf
authors.initials: R
authors.lastname: Rossaint
authors.forename: Yoram
authors.initials: Y
authors.lastname: Kluger
authors.forename: Bruno
authors.initials: B
authors.lastname: Riou
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D005167:Factor VII / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015942:Factor VIIa; D005260:Female; D006470:Hemorrhage / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D008297:Male; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D014949:Wounds, Nonpenetrating / Q000097:blood* / Q000188:drug therapy; D014950:Wounds, Penetrating / Q000097:blood* / Q000188:drug therapy
chemical_list: D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa