Benefix Pharmacology, Pharmacokinetics, Studies, Metabolism - Coagulation Factor IX (Recombinant)

Benefix Pharmacology, Pharmacokinetics, Studies, Metabolism - Coagulation Factor IX (Recombinant)

CLINICAL PHARMACOLOGY

Factor IX is activated by factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed.

Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of BeneFIX®, Coagulation Factor IX (Recombinant), increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients.

After single intravenous (IV) doses of 50 I.U./kg of BeneFIX®, Coagulation Factor IX (Recombinant), in 36 patients, each given as a 10-minute infusion, the mean increase in circulating factor IX activity was 0.8 ± 0.2 I.U./dL per I.U./kg infused (ranged from 0.4 to 1.4 I.U./dL per I.U./kg) and the mean biologic half-life was 19.4 ± 5.4 hours (ranged from 11 to 36 hours). The in vivo recovery using BeneFIX® was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. There was no significant difference in biological half-life. In subsequent evaluations at 6 and 12 months, the pharmacokinetic parameters were similar to the initial results.

In clinical studies of BeneFIX® involving a total of 64 patients (44 previously treated patients [PTPs], 11 previously untreated patients [PUPs], and the 9 patients participating only in the surgical study), more than 7 million I.U. were administered over a period of up to 18 months. This includes 57 HIV-negative and 7 HIV-positive patients. Forty-five patients were evaluated for efficacy, all of whom were treated successfully for bleeding episodes on an on-demand basis or for the prevention of bleeds. Bleeding episodes that were managed successfully included hemarthroses and bleeding in soft tissue and muscle.

Management of hemostasis was evaluated in the surgical setting. Thirteen surgical procedures have been performed in 12 patients, with a cumulative dose ranging from 10,000 to 348,000 I.U. The 10 major procedures were performed using a pulse replacement regimen (N=7) or a continuous infusion regimen (N=3), and included a liver transplantation, a hernia repair, six orthopedic surgeries, and two dental extractions. Circulatory factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens. Hemostasis was maintained throughout the surgical period, however, one patient required evacuation of a surgical wound site hematoma and another patient who received BeneFIX® after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of these patients. In four patients for whom fibrinopeptide A and prothrombin fragment 1 + 2 were measured pre-infusion, at 4 to 8 hours, and then daily up to 96 hours, there was no evidence of significant increase in coagulation activation. Data from two additional patients were judged to be not evaluable.

A study of BeneFIX® has been initiated in patients who had not been treated previously with plasma-derived factor IX concentrate (PUPs). In preliminary data, 11 of the 20 patients enrolled in the study received at least one infusion of BeneFIX®. These 11 patients received a total of 27,208 I.U. in 42 infusions. Thirty to 50 patients will be enrolled and followed for up to 5 years to complete evaluation of BeneFIX® in this patient population for safety, efficacy, and immunogenicity.

A low-level inhibitor developed in 1 of 44 BeneFIX® patients who had previously received plasma-derived products. This patient had an extensive previous history of exposure to plasma-derived factor IX products, including a single subcutaneous exposure, without history of inhibitor development. Antibodies were detected in this patient after 9 months of treatment (39 exposure days) with BeneFIX®. This patient was able to continue treatment with BeneFIX® with no anamnestic rise in inhibitor or anaphylaxis.