Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding

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 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. 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.