Pharmacokinetics of Factor VII
Authors: Morfini Massimo , Martinowitz Uriel , Batorova Angelika , Dolce Alberto , Napolitano Mariasanta , Ingerslev Jorgen , Schved Jean-Francois , Mariani Guglielmo 
Published: October 2019

Abstract
Abstract 2259

Introduction:
In Congenital Bleeding Disorders (CBD), efficacy of Replacement Therapy (RT) can be indirectly measured on the basis of pharmacokinetic (PK) methods. Therapeutic concentrations of clotting factors in the blood-stream at a given time depend on the dose and frequency of RT and the fall off patterns specific for each clotting factor (i.e. PK properties). The issue of the frequency of RT administration is particularly relevant in Factor VII (FVII) deficiency, a CBD characterized by the lack of a rare protein with a very short half-life. Recombinant FVIIa (rFVIIa), plasma-derived FVII (pdFVII) concentrates and Fresh Frozen Plasma (FFP) are used for on-demand or prophylaxis replacement despite reported half-lives in the range of 2–5 hours. Very limited information is available with reference to the pharmacokinetic parameters of infused FVII in FVII deficiency. The same holds for the In Vivo Recovery (IVR). In this study, we evaluated the PK of rFVIIa in 11 severe (FVIIc <2%) FVII deficient patients. Further, evaluation of “incremental” IVR was performed in 116 patients with a FVII deficiency (90 for rFVIIa, 19 for pdFVII concentrates and 7 for FFP).

Methods & Results:
Eleven severe FVII-deficient individuals in the non-bleeding state were given rFVIIa doses ranging from 16 to 24 μg/Kg/bw (mean 19.7, median 20). Pharmacokinetic parameters of rFVIIa were analyzed with reference to FVIIc post-infusion levels. Analyses of the PK parameters are detailed in Tab. 1. In Tab. 2 results regarding the IVR analyses of rFVIIa, pdFVII and FFP are reported, on the basis of FVIIc 15' after replacement. IVR data were also evaluated with reference to the baseline FVIIc, age and FVII mutation zygosity.

Conclusions:
PK data are characterized by an optimal correspondence between FVIIc levels and time; data variability is ample considering that all individuals were adults or teen-agers. Terminal half-life appeared longer than the Mean Residence Time (MRT) or T1/2, a data that can be interpreted as a reduction of the factor flow from the plasma pool to the extravascular space at the end of the fall off curve; this is confirmed by the Apparent volume of distribution based on the terminal phase (Vz) that is higher than the Apparent Volume of distribution at equilibrium (Vss). MRT and T1/2 are in keeping with previous studies and appear lower than those already reported for the pdFVII concentrates. Quite variable is also the Clearance (CL) showing that metabolic degradation and/or FVIIa vascular uptake greatly differ among patients. The latter aspect points towards the need for a CL individualized evaluation for patients who are eligible for continuous infusion protocols. Incremental IVRs of rFVIIa and FFP were lower (p< 0.001) than those calculated for the pdFVII concentrates. The difference between the recoveries of rFVIIa and pdFVII can either be ascribed to the FVIIc assay (only FVIIa assayed in the case of rFVIIa administration, FVII zymogen and FVIIa assayed in the case of pdFVII concentrates), to a more rapid disappearance rate of FVIIa from the vascular compartment or, finally, to a more rapid uptake by the FVIIa receptors (TF on the pericytes and the PC receptor on the endothelial cells). No difference was found between IVRs in children and adults nor between individuals with baseline FVIIc <2% or ≥ 2%. Also, no differences were found between patients homozygous or compound heterozygous for FVII gene lesions.

Disclosures:
No relevant conflicts of interest to declare.