Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: blood coagulation factors, ATC code: B02BD03.

Although FEIBA was developed in the early seventies and its factor VIII inhibitor bypassing activity has been proven in vitro as well as in vivo, its mode of action is still the subject of scientific discussion. FEIBA, as found with activity assays, is composed of prothrombin complex zymogens which are both procoagulant (prothrombin FVII, FIX, FX) and anticoagulant (protein C) in relatively equal quantities to the arbitrary FEIBA potency unit but its procoagulant enzyme content is relatively low. FEIBA, thus, contains the proenzymes of the prothrombin complex factors, but only very small amounts of their activation products, with the contents of FVIIa being the highest. [Turecek PL and Schwarz HP. Chapter 4: Factor Eight Inhibitor Bypassing Activity, in Production of Plasma Proteins for Therapeutic Use, eds. Joseph Bertolini, Neil Goss, John Curling, Wiley 2013, ISBN: 978-0-470-92431-0].

Current scientific works point to the role of specific components of the activated prothrombin complex, prothrombin (F II) and activated factor X (FXa) in the mode of action of FEIBA. [Turecek PL, Varadi K, Gritsch H, et al. Factor Xa and Prothrombin: Mechanism of Action of FEIBA. Vox Sang. 77: 72-79, 1999] FEIBA controls bleeding by induction and facilitation of thrombin generation, a process for which the formation of the prothrombinase-complex is crucial. A number of biochemical in vitro and in vivo studies have shown that FXa and prothrombin play a critical role in the activity of FEIBA. The prothrombinase complex has been found to be a major target site for FEIBA. Apart from prothrombin and FXa, FEIBA contains other proteins of the prothrombin complex, which could also facilitate haemostasis in hemophilia patients with inhibitors.

Treatment of hemophilia B patients with inhibitors
The experience in hemophilia B patients with factor IX inhibitors is limited due to the rarity of the disease.
Five hemophilia B patients with inhibitors were treated with FEIBA during clinical trials either on-demand, prophylactically or for surgical interventions:

In a prospective open-label, randomized, parallel clinical study in hemophilia A or B patients with persistent high-titer inhibitors (090701, PROOF), 36 patients were randomized to either 12 months ± 14 days of prophylactic or on-demand therapy. The 17 patients in the prophylaxis arm received 85 ± 15 U/kg FEIBA administered every other day and the 19 patients in the on-demand arm were treated individually determined by the physician. Two hemophilia B patients with inhibitors were treated in the on-demand arm and one hemophilia B patient was treated in the prophylactic arm.
The median ABR (annualized bleeding rate) for all types of bleeding episodes in patients in the prophylaxis arm (median ABR = 7.9) was less than that of patients in the on-demand arm (median ABR = 28.7), which amounts to a 72.5% reduction in median ABRs between treatment arms.




In another completed prospective non-interventional surveillance study of the perioperative use of FEIBA (PASS-INT-003, SURF) a total of 34 surgical procedures were performed in 23 patients. The majority of patients (18) were congenital hemophilia A patients with inhibitors, two were hemophilia B patients with inhibitors and three were patients with acquired hemophilia A with inhibitors. The duration of FEIBA exposure ranged from 1 to 28 days, with a mean of 9 days and a median of 8 days. The mean cumulative dose was 88,347 U and the median dose was 59,000 U. For hemophilia B patients with inhibitors, the longest exposure to FEIBA was 21 days and the maximum dose applied was 7324 U.

In addition, 36 case reports are available when FEIBA was used for treatment and prevention of bleeding episodes in hemophilia B patients with factor IX inhibitor (24 hemophilia B patients with inhibitors were treated on-demand, four hemophilia B patients with inhibitors were treated prophylactically and eight hemophilia B patients with inhibitors were treated for surgical procedures).

There are also isolated reports on the use of FEIBA in the treatment of patients with acquired inhibitors to factors X, XI and XIII.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
As the mode of action of FEIBA is still being discussed, it is not possible to make a conclusive statement about the pharmacokinetic properties.