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Recombinate (Antihemophilic Factor) - Description and Clinical Pharmacology

 
 



DESCRIPTION

RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is a glycoprotein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line. In culture, the CHO cell line secretes recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium utilizing a series of chromatography columns. A key step in the purification process is an immunoaffinity chromatography methodology in which a purification matrix, prepared by immobilization of a monoclonal antibody directed to factor VIII, is utilized to selectively isolate the rAHF in the medium. The synthesized rAHF produced by the CHO cells has the same biological effects as Antihemophilic Factor (Human) [AHF (Human)]. Structurally the protein has a similar combination of heterogenous heavy and light chains as found in AHF (Human).

RECOMBINATE rAHF is formulated as a sterile, nonpyrogenic, off-white to faint yellow, lyophilized powder preparation of concentrated recombinant AHF for intravenous injection. RECOMBINATE rAHF is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximum amounts: 12.5 mg/mL Albumin (Human), 0.20 mg/mL calcium, 1.5 mg/mL polyethylene glycol (3350), 180 mEq/L sodium, 55 mM histidine, 1.5 µg/AHF International Unit (IU) polysorbate-80. Von Willebrand Factor (vWF) is coexpressed with the Antihemophilic Factor (Recombinant) and helps to stabilize it. The final product contains not more than 2 ng vWF/IU rAHF which will not have any clinically relevant effect in patients with von Willebrand's disease. The product contains no preservative.

Manufacturing of RECOMBINATE rAHF is shared by Baxter Healthcare Corporation and Genetics Institute, Inc. The recombinant Antihemophilic Factor Concentrate (For Further Manufacturing Use), is produced by Baxter Healthcare Corporation and Genetics Institute (For Further Manufacturing Use) and subsequently formulated and packaged at Baxter Healthcare Corporation.

Each bottle of RECOMBINATE rAHF is labeled with the AHF activity expressed in IU per bottle. Biological potency is determined by an in vitro assay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.

CLINICAL PHARMACOLOGY

AHF is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized by hemorrhages which may occur spontaneously or after minor trauma. The administration of RECOMBINATE rAHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-nine (69) patients revealed the circulating mean half-life for rAHF to be 14.6 ± 4.9 hours (n=67), which was not statistically significantly different from plasma-derived HEMOFIL M, Antihemophilic Factor (Human) (AHF) (pdAHF). The mean half-life of HEMOFIL M AHF was 14.7 ± 5.1 hours (n=61). The actual baseline recovery observed with rAHF was 123.9 ± 47.7 IU/dl (n=23) which is significantly higher than the actual HEMOFIL M AHF baseline recovery of 101.7 ± 31.6 IU/dl (n=61). However, the calculated ratio of actual to expected recovery with rAHF (121.2 ± 48.9%) is not different on average from HEMOFIL M AHF (123.4 ± 16.4%). The clinical study of rAHF in previously treated patients (individuals with hemophilia A who had been treated with plasma derived AHF) was based on observations made on a study group of 69 patients. These individuals received cumulative amounts of Factor VIII ranging from 20,914 to 1,383,063 IU over the 48 month study. Patients were given a total of 17,700 infusions totaling 28,090,769 IU rAHF.

These patients were successfully treated for bleeding episodes on a demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding episodes successfully managed include hemarthroses, soft tissue and muscle bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24 procedures on 13 patients were performed during this study. These included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy and liver transplant) procedures. Hemostasis was maintained perioperatively and postoperatively with individualized AHF replacement.

A study of rAHF in previously untreated patients was also performed as part of an ongoing study. The study group was comprised of seventy-nine (79) patients, of whom seventy-six (76) had received at least one infusion of rAHF. To date, this cohort has been given 12,209 infusions totaling over 11,277,043 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.

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