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Kogenate (Antihemophilic Factor (Recombinant)) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Kogenate® FS Antihemophilic Factor (Recombinant) is a sterile, stable, purified, nonpyrogenic, dried concentrate that has been manufactured using recombinant DNA technology. Kogenate FS is intended for use in the treatment of classical hemophilia (hemophilia A), and is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII (FVIII) gene has been introduced. 1 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a highly purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as FVIII derived from human plasma. Compared to its predecessor product KOGENATE® Antihemophilic Factor (Recombinant), Kogenate FS incorporates a revised purification and formulation process that eliminates the addition of Albumin (Human).

The purification process includes an effective solvent/detergent virus inactivation step in addition to the use of the classical purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant FVIII and remove contaminating substances.

Kogenate FS is formulated with sucrose (0.9-1.3%), glycine (21-25 mg/mL), and histidine (18-23 mM) as stabilizers in the final container in place of Albumin (Human) as used in KOGENATE, and is then lyophilized. The final product also contains calcium chloride (2-3 mM), sodium (27-36 mEq/L), chloride (32-40 mEq/L), polysorbate 80 (not more than [NMT] 96 µg/mL), imidazole (NMT 20 µg/1000 IU), tri-n-butyl phosphate (NMT 5 µg/1000 IU), and copper (NMT 0.6 µg/1000 IU). The product contains no preservatives. The amount of sucrose in each vial is 28 mg. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels.

Each vial of Kogenate FS contains the labeled amount of recombinant FVIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation FVIII, human, is approximately equal to the level of FVIII activity found in 1 mL of fresh pooled human plasma.

Kogenate FS must be administered by the intravenous route.

CLINICAL PHARMACOLOGY

Pharmacokinetic studies were conducted in 20 patients with severe hemophilia A in North America. In this comparative pharmacokinetic study, Kogenate® FS Antihemophilic Factor (Recombinant) was shown to be similar to its predecessor product KOGENATE® Antihemophilic Factor (Recombinant) (rFVIII). Mean FVIII recovery measured 10 minutes following infusion was 2.1 ± 0.3 %/IU/kg for Kogenate FS and 2.4 ± 0.7 %/IU/kg for KOGENATE. The two recoveries were not statistically different (confidence interval 0.815-1.01). The mean biological half-life of recombinant FVIII formulated with sucrose (rFVIII-FS) is similar to KOGENATE with a mean of approximately 13 hours, which has previously been shown to be similar to plasma-derived Antihemophilic Factor (AHF). The activated partial thromboplastin time shortened appropriately with both rFVIII and rFVIII-FS. The recovery and half-life data for rFVIII-FS were unchanged after 24 weeks of exclusive treatment indicating continued efficacy and no evidence of FVIII inhibition. The mean FVIII recovery measured 10 minutes following a dose of rFVIII-FS in 37 patients (after 24 weeks of treatment with rFVIII-FS) was 2.1%/IU/kg, which was unchanged from FVIII recovery determined at baseline and at weeks 4 and 12.

Seventy-one patients with severe hemophilia A, ages 12-59, who had been previously treated with other recombinant and with plasma-derived AHF products, were enrolled in 6-month studies of home therapy with rFVIII-FS in Europe and North America. A total of 3995 infusions have been administered under this portion of the study, or 7.4 million units of rFVIII-FS. Treatment of 659 bleeding episodes during the study period required 951 infusions of rFVIII-FS. The majority of bleeding episodes (89.5%) were treated successfully with one or two infusions, using a mean dosage of approximately 28 IU/kg per treatment infusion. Regularly scheduled treatment accounted for 76% of infusions administered on study. Nine patients have received rFVIII-FS on 11 occasions for surgical procedures. The procedures included removal of a brain tumor, two total knee replacements, two joint synovectomies (one with Achilles tendon lengthening), two circumcisions, a hernia repair, and three teeth extractions. Hemostasis was satisfactory in all cases.

In clinical studies, Kogenate FS has been used in the treatment of bleeding episodes in previously untreated patients (PUPs) and minimally treated (MTP) pediatric patients. In ongoing studies, 61 PUPs/MTPs have been treated with Kogenate FS. Bleeding episodes were treated effectively with one or two infusions of rFVIII-FS. Ten patients have developed inhibitors. In these trials, approximately half of the patients have achieved 20 or more exposure days, and the incidence of inhibitor formation (16%) is consistent with that observed in other pediatric studies using plasma-derived and recombinant factor VIII products. 2-5

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