Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency.

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 µg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 µg/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.

Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study).

VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. 'Excellent'/'good' haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be 'excellent' for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.

Safety of Factor XIII Concentrate: Analysis of More than 20 Years of Pharmacovigilance Data.

BACKGROUND: Plasma-derived factor XIII (FXIII) concentrate is an effective treatment for FXIII deficiency. We describe adverse drug reactions (ADRs) reported during pharmacovigilance monitoring of Fibrogammin®/Corifact® and review published safety data. METHODS: Postmarketing safety reports recorded by CSL Behring from June 1993 to September 2013 were analyzed. Clinical studies published during the same period were also reviewed. RESULTS: Commercial data indicated that 1,653,450,333 IU FXIII concentrate were distributed over the review period, equivalent to 1,181,036 doses for a 70 kg patient. 75 cases were reported (one/15,700 standard doses or 22,046,000 IU). Reports of special interest included 12 cases of possible hypersensitivity reactions (one/98,400 doses or 137,787,500 IU), 7 with possible thromboembolic events (one/168,700 doses or 236,207,200 IU), 5 of possible inhibitor development (one/236,200 doses or 330,690,100 IU), and 20 of possible pathogen transmission (one/59,100 doses or 82,672,500 IU). 19 pathogen transmission cases involved viral infection; 4 could not be analyzed due to insufficient data, but for all others a causal relationship to the product was assessed as unlikely. A review of published literature revealed a similar safety profile. CONCLUSION: Assessment of ADRs demonstrated that FXIII concentrate carries a low risk of ADRs across various clinical situations, suggesting a favorable safety profile.

Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO®) in subjects with haemophilia A (SWIFT-HA study).

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.

Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate (Haemocomplettan P).

The objective of this study was to characterize the thrombogenicity of one pasteurized fibrinogen concentrate (Haemocomplettan P) in clinical use for over 20 years. Thrombus formation during venous stasis was assessed in rabbits receiving either 100 or 250 mg/kg Haemocomplettan P. Thrombotic adverse events possibly related to Haemocomplettan P were documented in a long-standing pharmacosurveillance program. A systematic review of thrombotic events in Haemocomplettan P clinical studies was also conducted. There was no evidence of thrombus formation during venous stasis in any Haemocomplettan P-treated animal. The pharmacosurveillance program spanned 22 years, during which a Haemocomplettan P quantity equivalent to more than 250 000 doses of 4 g each was distributed in 21 countries. Nine spontaneous reports of thrombotic adverse events possibly related to Haemocomplettan P were compiled, corresponding to an incidence rate of 3.48 events per 10 treatment episodes (95% confidence interval, 1.59-6.61 events per 10 treatment episodes). In 10 clinical studies involving 298 patients, one patient developed nonfatal venous thrombosis and pulmonary embolism to which fibrinogen concentrate may have contributed. Additionally, four other patients experienced arterial ischemic events that were likely attributable to massive hemorrhage and hypotension rather than fibrinogen replacement. Evidence from an animal model of venous stasis, a comprehensive pharmacosurveillance program, and a systematic review of clinical studies indicates that the thrombogenic potential of fibrinogen concentrate is low.

The safety of fibrin sealants.

Fibrin sealants are prepared from fibrinogen, thrombin and sometimes also factor XIII that have been purified from human plasma. Bovine aprotinin is also included in some preparations. Each of these components has the potential to carry blood-borne pathogens, albeit at a very low frequency. In order to minimize the risk of viral transmission from commercial fibrin sealants, plasma donations undergo a series of procedures that contribute to avoiding, inactivating and eliminating potential contaminants. The procedures for selection and screening of plasma donors, and the testing of donated plasma, incorporates highly sensitive molecular techniques (e.g. PCR testing) and contributes significantly to reducing the theoretical possibility of viral transmission. The starting material for bovine aprotinin is also carefully selected, and the manufacturing process rigorously assessed, to minimize the putative risk of transmission of bovine spongiform encephalopathies. The manufacturing process for commercial fibrin sealants comprises a range of procedures, including heat treatment (e.g. pasteurization, dry or vapor heating), filtration, solvent/detergent treatment, precipitation, pH treatment and chromatography. Some steps are an inherent part of the purification process and others (e.g. pasteurization, nanofiltration) are deliberately introduced to inactivate/eliminate potential pathogens. Current manufacturing processes provide a very high degree of safety for fibrin sealants. In 20 years of worldwide use, there have been no known cases of hepatitis or HIV transmission associated with the use of commercial fibrin sealants.