Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII ATC-Code: B02BD02
The factor VIII/ von Willebrand factor complex consists of two molecules (FVIII and vWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation.
Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin.
Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a results of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.


Previously untreated patients
The development of antibodies to FVIII occurs mainly in previously untreated patients (PUPs).
In a prospective, open-label study assessing the immunogenicity of Octanate in PUPs, 51 patients were included. 20 patients were primarily treated on demand and 31 patients were treated prophylactically. 44 patients met the criteria for assessing immunogenicity (i.e. >50 EDs and FVIII:C<1%). Inhibitors disappeared during regular Octanate treatment without a change in dose or treatment frequency in two out of five patients with inhibitors (one with a high-titer and one with a low-titer inhibitor). All inhibitors were detected in patients treated on-demand.
Mean times to high-titer and low-titer inhibitor development were 10 EDs (range 3-19) and 48 ED, respectively.


Octanate is being assessed for induction of immune tolerance induction (ITI) therapy in an ongoing observational clinical study.
In an interim analysis of the 69 patients so far treated with Octanate via ITI, 49 patients have completed the study. In the patients where the inhibitor was successfully eliminated, the monthly bleeding rates were significantly reduced.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties
Human plasma coagulation factor VIII (from the powder) is a normal constituent of the human plasma and acts like the endogenous factor VIII. After injection of the product, approximately two-thirds to three-quarter of the factor VIII remain in the circulation. The level of factor VIII activity reached in the plasma should be between 80% - 120% of the predicted factor VIII activity.
Plasma factor VIII activity decreases by a two-phase exponential decay. In the initial phase, distribution between the intravascular and other compartments (body fluids) occurs with a half- life of elimination from the plasma of 3 to 6 hours. In the subsequent slower phase (which probably reflects the consumption of factor VIII), the half-life varies between 8 to 20 hours, with an average of 12 hours. This corresponds to the true biological half-life.
For Octanate the following results were achieved for two pharmacokinetic studies with 10 and 14 haemophilia A patients, respectively:


Recovery         AUC*norm                                        Clearance Half-life      MRT*
(% x IU-1 x      (% x h x IU-1 x                                  (ml x h-1 x (h)           (h) kg)                kg)                                            kg) Study 1, n = 10
2.4 ± 0.36        45.5 ± 17.2       14.3 ± 4.01 19.6 ± 6.05       2.6 ± 1.21 Mean ± SD*
Study 2, n = 14
2.4 ± 0.25        33.4 ± 8.50       12.6 ± 3.03 16.6 ± 3.73       3.2 ± 0.88 Mean ± SD*

AUC* = area under the curve,
MRT* = mean residence time,
SD* = standard deviation