Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics: blood coagulation factor IX, ATC code: B02BD04.

Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin- K dependent coagulation factor and it is synthesised in the liver.
Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed.

Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX 

is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Of note, ABR (annualised bleeding rate) is not comparable between different factor concentrates and between different clinical studies.

In a multicentre, non-randomised, open-label clinical study, 22 patients aged 17-76 years with severe haemophilia B (≤2% activity) were treated either prophylactically (n=6) or on demand (n=16) for a median duration of 44 weeks. Patients on the prophylactic regimen (mean dose of 163 IU/kg per month per patient) experienced 11 bleeds on average during the study and the mean dose used to treat them was 49 IU/kg. Patients treated on demand experienced a mean of 13.4 bleeds during the study and the mean dose used to treat them was 30.4 IU/kg.

Paediatric population

In a multicentre, non-randomised, open-label clinical study in 15 children under 6 years of age (range 0.2-5.6 years) with severe haemophilia B (≤2% activity) for a median duration of 28 weeks. The mean number of bleeds per subject per month was 0.2 bleeds for patients in the prophylaxis group (n=10) and 1.2 bleeds in the on-demand group (n=6).

The mean dose of Replenine-VF for prophylaxis was 29 IU/kg (range: 20-37 IU/kg) given up to twice weekly; the mean monthly dose was 194 IU/kg. The mean dose to treat a bleed was 27 IU/kg (range: 13-53 IU/kg).

Inhibitors
The paediatric trial enrolled three previously untreated patients, all of whom remained inhibitor negative after treatment with Replenine-VF for 6 months. Overall, of the 67 previously tested patients in clinical studies, one young child developed an inhibitor with a titre of 3.6 Bethesda Units.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

In a clinical study of 15 adult patients with haemophilia B, the mean pharmacokinetic properties of Replenine-VF were as follows:

Parameter                        Mean
Incremental recovery             1.16
(IU/dl per IU/kg)
Area under curve (AUC0-56h)      15.2
(IU/ml/h)
Terminal half-life               19.0
(hours)
Initial (Alpha) half-life        4.8
(hours)
Elimination (Beta) half-life     20.9
(hours)
Mean Residence time              24.9
(hours)
Clearance                        4.52
(ml/hour/kg)
Volume of distribution           122.1
(ml/kg)


From clinical studies in 48 adult patients with haemophilia B, most of whom had several assessments of incremental recovery, all based on the maximum FIX:C in the first 1 hour (ISTH, 2001), the overall results were as follows:

Mean                        1.25 (95%CI 1.16 - 1.33) IU/dl per IU/kg
Median                      1.17 IU/dl per IU/kg

In a clinical trial of Replenine-VF given by continuous infusion to cover for major surgery, an initial bolus dose was given to raise the factor IX activity to about 100 IU/dl. Continuous infusion was then started at 6 IU/kg/hour (given undiluted by syringe pump or syringe driver). Subsequently, the rate of infusion was adjusted according to the following formula:

New rate = Latest rate x Target FIX level (IU/ml)
(IU/kg/hour) (IU/kg/hour)   Recently recorded FIX level (IU/ml)

The median clearance was fastest during the first 24 hours peri-operatively (Day 1). Thereafter, median clearance declined as follows: Day 1, 7.3 ml/kg/h; Day 2, 4.2 ml/kg/h; Day 3, 4.4 ml/kg/h; Day 4, 3.4 ml/kg/h; Day 5, 3.2 ml/kg/h; Day 6, 1.3 ml/kg/h. The formula describing the reduction in clearance from post-operative Days 2 to 8 was as follows:

Factor IX clearance (ml/h/kg) = 5.05 – (0.36 x day)

There was inter-patient variability in clearance so, when covering surgery by continuous infusion, monitoring of plasma factor IX activity is required (see section 4.2).

Additional data from the study of continuous infusion in major surgery provided the following mean pharmacokinetic values for the period on continuous infusion (by one-compartment multidose analysis):

Half-life:                  14.8 hours
Mean Residence Time:        31.3 hours
Clearance:                  3.8 ml/hour/kg
Volume of Distribution:     107.0 ml /kg