Research
Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding
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* Corresponding author: Bruno Riou bruno.riou@psl.aphp.fr
1 Department of Biomodelling, Novo Nordisk A/S, Maaloev, Denmark
2 Department of Biostatistics, Novo Nordisk A/S, Bagsvaerd, Denmark
3 Department of Surgery, Johannesburg Hospital, Houghton, Johannesburg, South Africa
4 Department of Surgery, National University Hospital, Singapore
5 Department of Surgery, Tygerberg Hospital, University of Stellenbosch, Tygerberg, South Africa
6 Departments of Surgery and Critical Care Medicine, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
7 Department of Anesthesiology, University Clinics, Aachen, Germany
8 Department of Surgery, Haifa Medical Center, Haifa, Israel
9 Department of Emergency Medicine and Surgery and Department of Anesthesiology and Critical Care, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; Université Pierre et Marie Curie-Paris 6, Paris, France
Critical Care 2006, 10:R104 doi:10.1186/cc4977
Published: 19 July 2006Abstract
Introduction
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 μg.kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 μg.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.kg-1.h-1; central volume of distribution 89 (32% CV) ml.kg-1; inter-compartmental clearance 24 ml.kg-1.h-1; and peripheral compartment volume 31 ml.kg-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U.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.
Conclusion
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.