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Koate-DVI (Antihemophilic Factor) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Antihemophilic Factor (Human), Koàte®-DVI, is a sterile, stable, purified, dried concentrate of human Antihemophilic Factor (AHF, factor VIII, AHG) which has been treated with tri-n-butyl phosphate (TNBP) and polysorbate 80 and heated in lyophilized form in the final container at 80°C for 72 hours. Koàte-DVI is intended for use in therapy of classical hemophilia (hemophilia A).

Koàte-DVI is purified from the cold insoluble fraction of pooled fresh-frozen plasma by modification and refinements of the methods first described by Hershgold, Pool, and Pappenhagen. 1 Koàte-DVI contains purified and concentrated factor VIII. The factor VIII is 300-1000 times purified over whole plasma. Part of the fractionation may be performed by another licensed manufacturer. When reconstituted as directed, Koàte-DVI contains approximately 50-150 times as much factor VIII as an equal volume of fresh plasma. The specific activity, after addition of Albumin (Human), is in the range of 9-22 IU/mg protein. Koàte-DVI must be administered by the intravenous route.

Each bottle of Koàte-DVI contains the labeled amount of antihemophilic factor activity in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of AHF found in 1.0 mL of fresh pooled human plasma. The final product when reconstituted as directed contains not more than (NMT) 1500 µg/mL polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25 µg/mL polysorbate 80, NMT 5 µg/g tri-n-butyl phosphate (TNBP), NMT 3 mM calcium, NMT 1 µg/mL aluminum, NMT 0.06 M histidine, and NMT 10 mg/mL Albumin (Human).

CLINICAL PHARMACOLOGY

Hemophilia A is a hereditary bleeding disorder characterized by deficient coagulant activity of the specific plasma protein clotting factor, factor VIII. In afflicted individuals, hemorrhages may occur spontaneously or after only minor trauma. Surgery on such individuals is not feasible without first correcting the clotting abnormality. The administration of Koàte-DVI provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients.

After infusion of Antihemophilic Factor (Human), there is usually an instantaneous rise in the coagulant level followed by an initial rapid decrease in activity, and then a subsequent much slower rate of decrease in activity.2-4 The early rapid phase may represent the time of equilibration with the extravascular compartment, and the second or slow phase of the survival curve presumably is the result of degradation and reflects the true biologic half-life of the infused Antihemophilic Factor (Human). 3

The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses during the manufacturing process for Koàte-DVI have been validated in laboratory studies at Bayer Corporation. Studies performed with the model enveloped viruses indicated that the greatest reduction was achieved by TNBP/polysorbate 80 treatment and 80°C heat. For this reason, VSV (Vesicular Stomatitis Virus, model for RNA enveloped viruses) and HIV-1 (Human Immunodeficiency Virus Type 1) were studied only at these two steps of the manufacturing process. The efficacy of the dry heat treatment was studied using all of the viruses, including BVDV (Bovine Viral Diarrheal Virus, model for hepatitis C virus) and Reo (Reovirus Type 3, model for viruses resistant to physical and chemical agents, such as hepatitis A), and the effect of moisture content on the inactivation of HAV (Hepatitis A Virus), PPV (Porcine Parvovirus, model for parvovirus B19), and PRV (Pseudorabies Virus, model for hepatitis B virus) was investigated.

Table I. Summary of In Vitro Log10 Viral Reduction Studies
    Enveloped Model Viruses Non-enveloped Model Viruses
HIV-I BVDV PRV VSV Reo HAV PPV
Model for HIV-1/2 HCV HBV RNA enveloped
viruses
HAV and viruses resistant to chemical and physical agents HAV B19
Global Reduction Factor 9.4 10.3 9.5 10.9 9 4.5 3.7

Similar studies have shown that a terminal 80°C heat incubation for 72 hours inactivates non-lipid enveloped viruses such as hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses such as hepatitis C. 7

Koàte-DVI is purified by a gel permeation chromatography step serving the dual purpose of reducing the amount of TNBP and polysorbate 80 as well as increasing the purity of the factor VIII.

A two-stage clinical study using Koàte-DVI was performed in individuals with hemophilia A who had been previously treated with other plasma-derived AHF concentrates. In Stage I of the pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koàte-DVI is bioequivalent to the unheated product, Koàte®-HP. The incremental in vivo recovery ten minutes after infusion of Koàte-DVI was 1.90% IU/kg (Koàte-HP 1.82% IU/kg). Mean biologic half-life of Koàte-DVI was 16.12 hours (Koàte-HP 16.13 hours). In Stage II of the study, participants received Koàte-DVI treatments for six months on home therapy with a median of 54 days (range 24-93). No evidence of inhibitor formation was observed, either in the clinical study or in the preclinical investigations. 2

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