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

Abstract

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.

Figures

Figure 1

Factor VII (FVII) coagulant activity measurements in recombinant FVIIa-treated blunt (n = 6) and penetrating (n = 15) trauma patients. One outlier was excluded from the population pharmacokinetic model data set.

Figure 2

Correlation between clearance and red blood cell (RBC) transfusion requirement after first dose of recombinant factor VIIa (rFVIIa). Plot of model-estimated, individual clearance versus measured post-dose RBC requirement (n= 123). R-squared value reflects the fraction of the variation in individual predicted clearance values explained by the model. P value reflects the significance level at which the hypothesis of no effect of RBC transfusion need after rFVIIa dosing on individual clearance was rejected. Dotted lines indicate 95% confidence interval of the regression curve.

Figure 3

Population factor VII (FVII) coagulant activity profile modeled from the study dosing regimen. Dots represent the observed FVII coagulant activities from both frequent and sparse sampling while the solid line is trauma average population profile for multiple dosing. This model shows dosing in an adult hemophilia population superimposed for comparison (see Materials and methods).

Figure 4

Population pharmacokinetics profiles simulated at various red blood cell (RBC) transfusion requirements (20, 30, and 40 units after dosing) – increasing transfusion requirement linked with increasing clearance. The full line depicts the global trauma population (Trauma, mean of 8.7 RBC units) Data for a hemophilia population has been superimposed for comparison(see Materials and methods).