Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02.

The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von Willebrand Factor) with different physiological functions. ADVATE contains recombinant coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII glycoprotein found in human plasma.

Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are increased by replacement therapy, thereby enabling a temporary correction of the factor VIII deficiency and correction of the bleeding tendency.


Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed ITI therapy. Data show that immune tolerance may be achieved.

In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen (20 to 40 IU/kg every 48 ±6 hours, n=30). The        pharmacokinetic guided dosing regimen (according to a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter- dosing interval of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are comparable in terms of reduction of bleeding rate.


The European Medicines Agency has waived the obligation to submit the results of studies with ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was conducted in a central laboratory using a one-stage clotting assay.
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize PK parameters, where age was defined as age at time of PK infusion.

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A (baseline factor VIII < 1%)
Parameter       Infants     Children          Older           Adolescents     Adults (mean ±         (n=5)       (n=30)          Children           (n=33)       (n=109) standard                                     (n=18) deviation)

Total AUC             1362.1 ±        1180.0 ±       1506.6 ± 530.0        1317.1 ±         1538.5 ± 519.1 (IU·h/dl)               311.8           432.7                                438.6 Adjusted              2.2 ± 0.6       1.8 ± 0.4           2.0 ± 0.5        2.1 ± 0.6            2.2 ± 0.6 Incremental
Recovery at
Cmax (IU/dL per IU/kg)a
Half-life (h)         9.0 ± 1.5       9.6 ± 1.7        11.8 ± 3.8         12.1 ± 3.2           12.9 ± 4.3 Maximum                110.5 ±       90.8 ± 19.1      100.5 ± 25.6       107.6 ± 27.6         111.3 ± 27.1 Plasma                  30.2
Concentration
Post Infusion
(IU/dl)
Mean Residence        11.0 ± 2.8     12.0 ± 2.7         15.1 ± 4.7         15.0 ± 5.0          16.2 ± 6.1 Time (h)
Volume of             0.4 ± 0.1       0.5 ± 0.1           0.5 ± 0.2        0.6 ± 0.2            0.5 ± 0.2 Distribution at
Steady State
(dl/kg)
Clearance             3.9 ± 0.9       4.8 ± 1.5           3.8 ± 1.5        4.1 ± 1.0            3.6 ± 1.2 (ml/kg*h) a
Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post- infusion Factor VIII measurement.

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma volume per kilogram body weight in younger patients.

Pharmacokinetic data with ADVATE on previously untreated patients are currently not available.