Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency
Hematology (Amsterdam, Netherlands). 2020;25(1):17-25
Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP.Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency. Patients received their routine FVII product (30 IU/kg plasma-derived FVII [pdFVII] or 25 mug/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 mug/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48 hr after administration. FVIIa activity was determined using a one-stage clotting assay. PD parameters were derived from thrombin generation testing, using the Nijmegen hemostasis assay.Results: rVIIa-FP showed improved PK compared to rFVIIa, with 2- to 3-fold longer t1/2 and 4- to 8-fold lower clearance. Analysis of PD data showed a sustained suppression of lag time below 4.5 min (upper limit of healthy people) for rVIIa-FP compared to rFVIIa. AUEC and ECmax were similar across the two dose groups of rVIIa-FP and rFVIIa.Discussion: rVIIa-FP was well tolerated in patients with congenital FVII deficiency, showed a longer half-life and lower clearance compared to rFVIIa, and lag time remaining within healthy ranges for ≥8 hr.Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.
Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO) in subjects with haemophilia A (SWIFT-HA study)
Thrombosis Research.. 2016;137:119-25.
INTRODUCTION VONCENTO (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate P (CSL Behring). METHODS The pharmacokinetic, efficacy and safety profiles of VONCENTO were investigated in this multicentre,double-blind, randomised study. Subjects aged > 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO or BIOSTATE reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for > 6 months and > 50 exposure days, respectively. RESULTS Besides the confirmation of bioequivalence between VONCENTO and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO was well tolerated and no inhibitory antibodies were identified during the study period. CONCLUSIONS This study demonstrated the bioequivalence of VONCENTO to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.