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Riastap (Fibrinogen Human) - Description and Clinical Pharmacology

 
 



DESCRIPTION

RiaSTAP is a heat-treated, lyophilized fibrinogen (coagulation factor I) powder made from pooled human plasma.

Each vial contains 900 to 1300 mg fibrinogen, 400 to 700 mg human albumin, 375 to 660 mg L-arginine hydrochloride, 200 to 350 mg sodium chloride and 50 to 100 mg sodium citrate. Sodium hydroxide and hydrochloric acid may have been used to adjust the pH.

All plasma used in the manufacture of RiaSTAP is tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. Additionally, the plasma is tested with FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be non-reactive (negative). For HBV, an investigational NAT procedure is used; however, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for HAV and B19V. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.

RiaSTAP is manufactured from cryoprecipitate into a glycine precipitate, which is then further purified by multiple precipitation/adsorption steps. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: cryoprecipitation, A1(OH)3 adsorption/glycine precipitation/A1(OH)3 adsorption, heat treatment (+60ºC for 20 hours in an aqueous solution), and two subsequent glycine precipitation steps (initial and main glycine precipitation steps). These steps have been validated independently in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 1 shows the virus clearance during the manufacturing process for RiaSTAP, expressed as the mean log10 reduction factor (LRF).

Table 1: Cumulative (Log10) Virus Inactivation/Reduction in RiaSTAP
Manufacturing Step Virus Reduction Factor (log10)
Enveloped viruses Non-enveloped viruses
HIV BVDV WNV HSV-1 PRV HAV CPV B19V 1
BVDV, bovine viral diarrhea virus, model for HCV
WNV, West Nile virus
HSV-1, herpes simplex virus type 1
CPV, canine parvovirus, model for B19V
n.d., not done
Cryoprecipitation n.d. n.d. n.d. 1.6PRV – as HSV-1 a herpes virus – is reduced by cryoprecipitation by 1.6 log10 2.4 2.8 n.d.
Al(OH)3 adsorption/ glycine precipitation/ Al(OH)3 adsorption (2.8) 2 (1.5) n.d. (0.9) n.d.
Heat Treatment ≥ 5.7 ≥ 9.1 ≥ 8.3 ≥ 8.1 ≥ 4.3 1.6 ≥ 4.5
Glycine precipitation
(two subsequent steps)
3.9 2.1 n.d. 1.0 (1.0) (1.6) n.d.
Cumulative virus reduction (log10) ≥ 9.6 ≥ 11.2 ≥ 8.3 ≥ 9.1 1.6 ≥ 6.7 4.4 ≥ 4.5

1 B19V, human parvovirus B19, the virus elimination studies for parvovirus B19 employed a novel experimental infectivity assay utilizing clone of cell line UT7 that contains erythropoietic progeny cells. Virus titer was determined using an immunofluorescence-based detection method.
2 Not included in the calculation of the cumulative virus reduction factor.

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)

CLINICAL STUDIES

The pharmacokinetic study evaluated the single-dose PK (see Pharmacokinetics [12.3]) and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing. MCF was measured to demonstrate functional activity of replacement fibrinogen when a fixed dose of RiaSTAP was administered. Clot firmness is a functional parameter that depends on: activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for the assessment of fibrinogen content and for the effects of fibrinogen supplementation on clinical efficacy.5

For each subject, the MCF was determined before (baseline) and one hour after the single dose administration of RiaSTAP. RiaSTAP was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that the MCF values were significantly higher after administration of RiaSTAP than at baseline (see Table 3 ). The mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects < 16 years old and 8.5 mm for subjects ≥ 16 to < 65 years old). The mean change in MCF values closely approximated the levels expected from adding known amounts of fibrinogen to plasma in vitro. 6 Hemostatic efficacy in acute bleeding episodes, and its correlation with MCF, are being verified in a postmarketing study.

Table 3: MCF [mm] (ITT population)
Time point n Mean ± SD Median (range)
MCF = maximum clot firmness; mm = millimeter; ITT = intention-to-treat.
Pre-infusion 13 0 ± 0 0 (0-0)
1 hour post-infusion 13 10.3 ± 2.7 10.0 (6.5-16.5)
Mean change (primary analysis)p-value was <0.0001. 15The mean change was set to 0 for 2 subjects with missing MCF data. 8.9 ± 4.4 9.5 (0-16.5)

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