Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: CSL Behring GmbH, Emil-von-Behring-Strasse 76, 35041, Marburg, Germany
Pharmacotherapeutic group: antihaemorrhagics, human fibrinogen
ATC code: B02BB01
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 fibrin haemostatic clot.
The administration of human fibrinogen concentrate provides 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 PK (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 bw of Riastap. Riastap 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 post-marketing study.
Human fibrinogen is a normal constituent of human plasma and acts like endogenous fibrinogen. In plasma, the biological half-life of fibrinogen is 3 to 4 days. Regarding degradation, Riastap behaves like endogenous fibrinogen.
The product 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 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 [h•mg/ml] | 124.3 ± 24.16 | 126.8 (81.73-156.40) |
| 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 body weight] | 1.8 ± 0.35 | 1.7 (1.30-2.73) |
t1/2 = terminal elimination half-life, h = hour, Cmax = maximum concentration within 4 hours, AUC = area under the curve, Cl = clearance, MRT = mean residence time, Vss = volume of distribution at steady state, SD = standard deviation, IVR = in vivo recovery
Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity and safety pharmacology.
Preclinical studies with repeated dose applications (chronic toxicity, cancerogenicity and mutagenicity) cannot be reasonably performed in conventional animal models due to the development of antibodies following the application of heterologous human proteins.
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