25 Aug 06

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

Posted in Bleeding, rFVIIa at 8:59 by Laci

By T Klitgaard, RT y Palacios, KD Boffard, PTC Iau, B Warren et al for the NovoSeven® Trauma Study Group

Critical Care 2006, 10:R104

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.

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