Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, 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.

Current scientific works point to the role of specific components of the activated prothrombin complex, prothrombin (FII) and activated factor X (FXa) in the mode of action of FEIBA.

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 haemophilia patients with inhibitors.

Treatment of haemophilia B patients with inhibitors
The experience in haemophilia B patients with factor IX inhibitors is limited due to the rarity of the disease. Five haemophilia 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 haemophilia A or B patients with persistent high-titre 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 haemophilia 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 haemophilia A patients with inhibitors, two were haemophilia B patients with inhibitors and three were patients with acquired haemophilia 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 haemophilia B patients with inhibitors, the longest exposure to FEIBA was 21 days and the maximum dose applied was 7 324 U.

In addition, 48 patients in literature are reported when FEIBA was used for treatment and prevention of bleeding episodes in haemophilia B patients with factor IX inhibitor (34 haemophilia B patients with inhibitors were treated on-demand, six haemophilia B patients with inhibitors were treated prophylactically and eight haemophilia 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 IX, X, XI and XIII.
In rare cases, FEIBA was also used in patients with the presence of von Willebrand factor inhibitor.

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.