Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: C1-inhibitor, plasma derived
ATC code: B06AC01
C1-esterase inhibitor is a plasma glycoprotein with a molecular weight of 105 kD and a carbohydrate moiety of 40 %. Its concentration in human plasma ranges around 240 mg/l.
Besides its occurrence in human plasma, also the placenta, the liver cells, monocytes and platelets contain C1-esterase inhibitor.

C1-esterase inhibitor belongs to the serine-protease-inhibitor-(serpin)-system of human plasma as do also other proteins like antithrombin III, alpha-2-antiplasmin, alpha-1- antitrypsin and others.

Under physiological conditions C1-esterase inhibitor blocks the classical pathway of the complement system by inactivating the enzymatic active components C1s and C1r. The active enzyme forms a complex with the inhibitor in a stoichiometry of 1 : 1.
Furthermore, C1-esterase inhibitor represents the most important inhibitor of the contact activation of coagulation by inhibiting factor XIIa and its fragments. In addition, it serves, besides alpha-2-macroglobulin, as the main inhibitor of plasma kallikrein.

The therapeutic effect of Berinert in hereditary angioedema is induced by the substitution of the deficient C1-esterase inhibitor activity.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The product is to be administered intravenously and is immediately available in the plasma with a plasma concentration corresponding to the administered dose.

The pharmacokinetic properties of Berinert have been investigated in two studies.

A phase I study conducted in 15 healthy, adult subjects provided PK data that was used to assess the relative bioavailability of Berinert 1500 and Berinert 500. Comparable bioavailability of the two presentations of Berinert was demonstrated. For C1-INH antigen concentrations the C and AUC geometric mean ratios (90% CIs) were 1.02 (0.99, 1.04) and max         0-last

1.02 (0.99, 1.05) respectively. Half-life was estimated in a subset of subjects using non- compartmental PK analyses. The mean half-life of Berinert 1500 and Berinert 500 was 87.7 hours and 91.4 hours, respectively.

Pharmacokinetic properties have been investigated in patients with hereditary angioedema (34 patients > 18 years, 6 patients < 18 years). These included 15 patients under prophylactic treatment (with frequent/severe attacks), as well as 25 patients with less frequent/mild attacks and "on demand" treatment. The data were generated in an attack-free interval.

The median in vivo recovery (IVR) was 86.7 % (range: 54.0 – 254.1 %). The IVR for children was slightly higher (98.2 %, range: 69.2 – 106.8 %) than for adults (82.5 %, range: 54.0 – 254.1 %). Patients with severe attacks had a higher IVR (101.4 %) compared to patients with mild attacks (75.8 %, range: 57.2 – 195.9 %).

The median increase in activity was 2.3%/IU/kg b.w. (range: 1.4 – 6.9 %/IU/kg b.w.). No significant differences were seen between adults and children. Patients with severe attacks showed a slightly higher increase in activity than patients with mild attacks (2.9, range: 1.4 – 6.9 vs. 2.1, range: 1.5 – 5.1 %/IU/kg b.w.).

The maximum concentration of human C1-esterase inhibitor activity in plasma was reached within 0.8 hours after administration of Berinert without significant differences between the patient groups.

The median half-life was 36.1 hours. It was slightly shorter in children than in adults (32.9 vs. 36.1 hours) and in patients with severe attacks than in patients with mild attacks (30.9 vs. 37.0).