CLINICAL PHARMACOLOGY
Mechanism of Action
Fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Fibrinogen is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B (FPA and FPB, respectively).2 FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers.2 The resulting fibrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.3 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall.
Pharmacodynamic Action
Administration of RiaSTAP to patients with congenital fibrinogen deficiency replaces the missing, or low coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
Pharmacokinetics
A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg RiaSTAP. Blood samples were drawn from the patients to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of RiaSTAP are summarized in Table 2.
No statistically relevant difference was observed between males and females for fibrinogen activity. Subjects less than 16 years of age (n=4) had shorter half-life (69.9 ± 8.5) and faster clearance (0.73 ± 0.14) compared to subjects >16 years of age. The number of subjects less than 16 years of age in this study limits statistical interpretations.
The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase patients' fibrinogen plasma concentration by approximately 120 mg/dL.
The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay).
Table 2: Pharmacokinetic Parameters (n=14) for Fibrinogen Activity Parameters | Mean ± SD (range) |
Half-life [hours] | 78.7 ± 18.13 (55.73-117.26) |
Cmax [mg/dL] | 140 ± 27 (100-210) |
AUC for dose of 70 mg/kg [mg*hr/mL] | 124.3 ± 24.16 (81.73-156.40) |
Clearance [mL/h/kg] | 0.59 ± 0.13 (0.45-0.86) |
Mean residence time [hours] | 92.8 ± 20.11 (66.14-126.44) |
Volume of distribution at steady state [mL/kg] | 52.7 ± 7.48 (36.22-67.67) |
|