Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect

Abstract

Determining the optimal frequency of replacement therapy is a clinically relevant issue in factor VII (FVII) deficiency, a bleeding disorder characterised by trace levels of a protein with a very short half-life.The main objective of this study was to clarify the discrepancy between the unfavourable PK data and positive clinical results obtained with rFVIIa.In Vivo Recovery (IVR) was determined in 56 patients using data from the Seven Treatment Evaluation Registry (STER) and a full PK analysis was performed in 10 severe FVII-deficient patients (FVII coagulant activity [FVII:C] <2%) in a non-bleeding state.When evaluated using FVII:C, the main study results were: i. low IVR (0.59 U dl -1 /U kg -1 ), ii. a very large volume of distribution at steady state (14.72 dl kg -1 ), iii.fast clearance (4.41 dl h kg -1 ), iv.very short half-life (2.12 h) and mean residence time (MRT) (3.05 h).Significantly (p <0.001) longer half-life (5.80 h) and MRT (8.38 hours) were obtained using a global assay, the Prothrombin Time ratio (PTr).The large volume of distribution of rFVIIa, approximately 40 times the plasma volume, the low IVR, the very short half-life and the fast clearance, indicate that a rapid and substantial diffusion towards the extravascular spaces occurs.The discrepancy between the FVII:C-and the PTr-related data indicate the presence of noticeable plasma clotting activity after rFVIIa infusion, when FVII:C is not detectable, consistent with the observation that prophylaxis is effective with less frequent administrations and low doses.