POPULATION PHARMACOKINETICS OF RECOMBINANT FACTOR VIIA IN VOLUNTEERS ANTICOAGULATED WITH ACENOCOUMAROL

This study establishes a population PK model for FVII clotting activit y (FVII:C) after injection of recombinant activated factor VII (rFVIIa ) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose rangin g from 5 to 320 mu g/kg. The FVII:C kinetic was fitted to a 2 compartm ent model, with continuous ''endogenous perfusion'' mimicking endogeno us activity. Estimated clearance was 2.4 Ik (20% inter-individual vari ability and 9% inter-period variability). The volume of distribution a t steady-state appeared to be significantly dose dependent: 78 ml/kg f or doses less than or equal to 20 mu g/kg and 88 ml/kg for doses >20 m u g/kg respectively, with 16% inter-individual variability. The dose p roducing 50% of the maximum drop of INR was estimated to be 2.2 mu g/k g. The model will be used to better define the dosage regimen for futu re clinical developments.