DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Artiss (Fibrinogen / Thrombin Human) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ARTISS [Fibrin Sealant], Vapor Heated, Solvent Detergent Treated, (ARTISS) is a two-component fibrin sealant made from pooled human plasma. When combined, the two components, Sealer Protein (Human) and Thrombin (Human), mimic the final stage of the blood coagulation cascade.

Sealer Protein (Human)

Sealer Protein (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Sealer Protein (Human) is provided either as a freeze-dried powder [Sealer Protein Concentrate (Human)] for reconstitution with Fibrinolysis Inhibitor Solution (Synthetic) or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe (1). The active ingredient in Sealer Protein (Human) is fibrinogen. A Fibrinolysis Inhibitor, Aprotinin (Synthetic) is included in the Sealer Protein (Human) component to delay fibrinolysis. Aprotinin (Synthetic) is manufactured by solid phase synthesis from materials completely of non-human/non-animal origin.

To obtain Sealer Protein (Human), cryoprecipitate derived from the plasma is washed, dissolved in buffer solution, solvent/detergent treated, vapor heat treated, sterile filtered and either freeze-dried in vials or frozen in pre-filled syringes.

Thrombin (Human)

Thrombin (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin (Human) is also provided either as a freeze-dried powder for reconstitution with Calcium Chloride Solution or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe (2).

Thrombin is prepared from plasma through a series of separation and filtration steps followed by incubation of the solution with calcium chloride to activate prothrombin to thrombin. The solution subsequently undergoes ultra/diafiltration, vapor heat treatment, solvent/detergent treatment, sterile filtration and either freeze-drying in vials or frozen in pre-filled syringes.

Sealer Protein (Human) and Thrombin (Human) are made from pooled human plasma collected at US licensed collection centers. The vapor heat and solvent/detergent treatment steps used in the manufacturing process have been shown to be capable of significant viral reduction. No procedure, however, has been shown to be completely effective in removing viral infectivity from derivatives of human plasma (see CLINICAL PHARMACOLOGY, Other Clinical Pharmacology Information and WARNINGS/PRECAUTIONS, Infection Risk from Human Plasma .

See DOSAGE FORMS AND STRENGTHS (3) .

CLINICAL PHARMACOLOGY

Mechanism of Action

Upon mixing Sealer Protein (Human) and Thrombin (Human), soluble fibrinogen is transformed into fibrin that adheres to the wound surface and to the skin graft to be affixed. Due to the low thrombin concentration, polymerization of ARTISS will take approximately 60 seconds.

Pharmacodynamics

Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein (Human) into fibrin (see Pharmacokinetics). Fibrinolysis Inhibitor, Aprotinin (Synthetic), is a polyvalent protease inhibitor that prevents premature degradation of fibrin. Free Aprotinin and its metabolites have a half-life of 30 to 60 minutes and are eliminated by the kidney. Preclinical studies with different fibrin sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.

Pharmacokinetics

Pharmacokinetic studies were not conducted. Because ARTISS is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.

Other Clinical Pharmacology Information

Viral Clearance

The manufacturing procedure for ARTISS includes processing steps designed to further reduce the risk of viral transmission. In particular, vapor heating and solvent/detergent treatment processes are included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The stock virus suspensions represent HIV, HBV, HCV, HAV and Human Parvovirus B19.

The virus reduction factors (expressed as log10) of independent manufacturing steps are shown in Table 3 for each of the viruses tested:

Table 3.
n.d. = not determined
HIV-1: Human immunodeficiency virus 1; HAV: Hepatitis A virus; BVDV: Bovine viral diarrhea virus, a model for Hepatitis C virus; PRV: Pseudorabies virus, a model for enveloped DNA viruses, among those Hepatitis B virus; MMV: Mice minute virus, a model for B19V.
Reduction Factors for Virus Removal and/or Inactivation
Sealer Protein Component
Mean Reduction Factors [log10] of Virus Tested
Manufacturing Step HIV-1 HAV BVDV PRV MMV
Early Manufacturing Steps n.d. n.d. n.d. n.d. 2.7
Solvent/Detergent Treatment >5.3 n.d. >5.7 >5.9 n.d.
Vapor Heat Treatment >5.5 >5.6 >5.7 >6.7 1.2
Overall Reduction Factor (ORF) >10.8 >5.6 >11.4 >12.6 3.9
Reduction Factors for Virus Removal and/or Inactivation
Thrombin Component
Mean Reduction Factors [log10] of Virus Tested
Manufacturing Step HIV-1 HAV BVDV PRV MMV
Thrombin precursor mass capture 3.2 1.5 1.8 2.5 1.2
Vapor Heat Treatment >5.5 >4.9 >5.3 >6.7 1.0
Solvent/Detergent Treatment >5.3 n.d. >5.5 >6.4 n.d.
Ion Exchange Chromatography n.d. n.d. n.d. n.d. 3.6
Overall Reduction Factor (ORF) >14.0 >6.4 >12.6 >15.6 5.8

In addition, Human Parvovirus B19 was used to investigate the upstream Thrombin precursor mass capture step, the Sealer Protein early manufacturing steps and the Thrombin and Sealer Protein vapor heating steps. Using quantitative PCR assays, the estimated log reduction factors obtained were 1.7 and 3.4 for the Thrombin precursor mass capture step and Sealer Protein early manufacturing steps and >4 / 1.0 for the Thrombin / Sealer Protein vapor heating steps, respectively.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of ARTISS or studies to determine the effect of ARTISS on fertility have not been performed.

CLINICAL STUDIES

ARTISS was investigated for adherence of split thickness sheet skin grafts in burn patients in a prospective, randomized, controlled, evaluator- blinded, multicenter clinical study. In each of the 138 patients, two comparable test sites were identified after burn wound excision. Skin grafts were adhered at one test site using ARTISS, and at the other test site using staples (control). The study product was applied once to the wound bed of the allocated test site during skin grafting surgery.

Of the 138 treated subjects, 94 (68.1%) were male and 44 (31.9%) were female. The mean SD age was 30.8 17.6 years; 19 (13.8%) subjects were ≤ 6 years old, 21 (15.2%) subjects were 7 to 18 years old, and 98 (71.0%) were > 18 years old. The mean SD estimated total body surface area (TBSA) for all burn wounds was 13.6 9.2%. The mean SD estimated TBSA requiring skin grafting was 8.0 6.9%. The mean SD estimated TBSA for ARTISS test sites was 1.7 0.8% and for the stapled test sites was 1.7 0.7%. Burn wound thickness was classified as full thickness in 106 (76.8%) of the 138 treated subjects, and partial thickness in 32 (23.2%) subjects. The mean SD volume applied was 2.7 1.9 mL (range: 0.2 to 12.0 mL). The mean SD surface area treated was 166.4 95.0 cm2 (range: 26.1 to 602. cm2). The mean SD calculated dosing volume was 1.8 1.1 mL/100 cm2 (range: 0.2 to 6.0 mL/100 cm2).

The safety population contained all 138 treated subjects; however, 11 subjects did not have an available primary endpoint assessment, leaving a modified intent-to-treat (ITT) set of 127 patients. Complete wound closure by Day 28 was achieved in 43.3% of the ARTISS test sites and 37.0% of the stapled test sites in the 127 ITT patients. The lower limit of the 97.5% confidence interval of the difference between ARTISS and staples was –0.029. A similar result was obtained in the per protocol (PP) population: complete wound closure by Day 28 was achieved in 45.3% of the ARTISS test sites and 39.6% of the stapled test sites in the 106 PP patients. The lower limit of the 97.5% confidence interval of the difference between ARTISS and staples was –0.041. Therefore, ARTISS was found to be non-inferior to staples in the ITT and PP populations at the 97.5% one-sided level for complete wound closure by Day 28 because the lower limit of the confidence interval of the difference between ARTISS and staples success rates was greater than the predefined limit of –0.1.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2012