Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, human fibrinogen,
ATC code: B02B B01

Human fibrinogen (coagulation factor I), in the presence of thrombin, activated coagulation factor XIII (F XIIIa) and calcium ions, is converted into a stable and elastic three- dimensional haemostatic fibrin clot.

The administration of human fibrinogen concentrate causes an increase in plasma fibrinogen level and can temporarily correct the coagulation defect of patients with fibrinogen deficiency.

The pivotal Phase II study evaluated the single-dose pharmacokinetics (see 5.2 Pharmacokinetic properties) and also provided efficacy data using the surrogate endpoint maximum clot firmness (MCF) and safety data.
For each subject, the MCF was determined before (baseline) and one hour after a single dose administration of 70 mg/kg body weight of Haemocomplettan. Haemocomplettan was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency (afibrinogenaemia) as measured by thromboelastometry. Haemostatic efficacy in acute bleeding episodes, and its correlation with MCF, are being verified in a postmarketing study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Human fibrinogen is a normal constituent of the human plasma and acts like endogenous fibrinogen. In plasma, the biological half-life of fibrinogen is 3 to 4 days. Regarding degradation Haemocomplettan behaves like the endogenous fibrinogen.

Haemocomplettan is administered intravenously and is immediately available in a plasma concentration corresponding to the dosage administered.

A pharmacokinetic study evaluated the single-dose pharmacokinetics before and after administration of human fibrinogen concentrate in subjects with congenital afibrinogenaemia. This prospective, open label, uncontrolled, multicentre study consisted of 5 females and 10 males, ranging in age from 8 to 61 years (2 children, 3 adolescents, 10 adults). The median dose was 77.0 mg/kg body weight (range 76.6 – 77.4 mg/kg).

Blood was sampled from 15 subjects (14 measurable) to determine the fibrinogen activity at baseline and up to 14 days after the infusion was complete. In addition, the incremental in vivo recovery (IVR, defined as the maximum increase in fibrinogen plasma levels per mg/kg body weight dosed), was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 (range 1.30-2.73) mg/dl per mg/kg body weight. The following table provides the pharmacokinetic results:

Pharmacokinetic results for fibrinogen activity

Parameter (n=14)                                 Mean ± SD           Median (range) t1/2 [h]                                         78.7 ± 18.13      77.1 (55.73-117.26) Cmax [g/l]                                        1.4 ± 0.27         1.3 (1.00-2.10) AUC for dose of 70 mg/kg                        124.3 ± 24.16      126.8 (81.73-156.40) [h•mg/ml]
Extrapolated part of AUC [%]                      8.4 ± 1.72         7.8 (6.13-12.14) Cl [ml/h/kg]                                      0.59 ± 0.13        0.55 (0.45-0.86) MRT [h]                                          92.8 ± 20.11      85.9 (66.14-126.44) Vss [ml/kg]                                       52.7 ± 7.48       52.7 (36.22-67.67) IVR [mg/dl per mg/kg bw]                          1.8 ± 0.35         1.7 (1.30-2.73) t1/2 = terminal elimination half-life h = hour
Cmax = maximum fibrinogen concentration in plasma within 4 hours
AUC = area under the plasma concentration curve
Cl = clearance
MRT = mean residence time
Vss = volume of distribution at steady state
SD = standard deviation
IVR = in vivo recovery bw= body weight