Refacto Pharmacology, Pharmacokinetics, Studies, Metabolism - Antihemophilic Factor

Refacto Pharmacology, Pharmacokinetics, Studies, Metabolism - Antihemophilic Factor

CLINICAL PHARMACOLOGY

Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). The administration of ReFacto® Antihemophilic Factor (Recombinant) increases plasma levels of factor VIII activity and can temporarily correct the in vitro coagulation defect in these patients.

Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with hemophilia A and therefore replacement therapy is necessary.

In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay , the circulating mean half-life for ReFacto was 14.5 ± 5.3 hours (ranged from 7.6-27.7 hours), which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human) (pdAHF), which had a mean half-life of 13.7 ± 3.4 hours (ranged from 8.8-23.7 hours). Mean incremental recovery (K-value) of ReFacto in plasma was 2.4 ± 0.4 IU/dL per IU/kg (ranged from 1.9-3.3 IU/dL per IU/kg). This was comparable to the mean incremental recovery observed in plasma for pdAHF which was 2.3 ± 0.3 IU/dL per IU/kg (ranged from 1.7-2.9 IU/dL per IU/kg). Results obtained from this controlled pharmacokinetic study, which used a central laboratory for the analysis of all plasma samples, showed that the one-stage factor VIII clotting assay gave results which were approximately 50% of the values obtained with the chromogenic assay.

In two additional clinical studies, pharmacokinetic parameters were evaluated for previously treated patients [PTPs] and previously untreated patients [PUPs]. In PTPs (n=87) ReFacto had a mean incremental recovery of 2.4 ± 0.4 IU/dL per IU/kg (ranged from 1.1-3.8 IU/dL per IU/kg) and an elimination half-life (n=67) of 10.7 ± 2.8 hours. In PUPs (n=45) ReFacto had a lower mean incremental recovery of 1.7 ± 0.4 IU/dL per IU/kg (ranged from 0.2-2.8 IU/dL per IU/kg) as compared to PTPs. Population pharmacokinetic modeling using data from 44 PUPs led to a mean estimated half-life of ReFacto in PUPs of 8.0 ± 2.2 hours. These parameters did not change over time (12 months) for PTPs or PUPs.

In clinical studies of ReFacto involving a total of 218 patients (117 PTPs including 4 who participated in the surgery study only, and 101 PUPs), more than 84 million IU were administered over a period of up to 54 months. The 117 PTPs were given a median of 230 injections (range of 4-1530 injections) over a median of 1200 days (range of 31-1640 days). The 101 PUPs were given a median of 26 injections (range of 1-490 injections) over a median of 830 days (range of 1-1298 days). One hundred thirteen PTPs and 99 PUPs were evaluated for efficacy in bleeding episodes. The 113 PTPs experienced a median of 54 bleeding episodes and the 99 PUPs experienced a median of 12 bleeding episodes. All were treated successfully on an on-demand basis or for the reduction of bleeding episodes except for one PTP and two PUPs who discontinued ReFacto treatment and switched to another product after the development of inhibitors. Bleeding episodes included hemarthroses, and bleeding in soft tissue, muscle, and other anatomical sites.

ReFacto has been studied in short-term routine prophylaxis. In uncontrolled clinical trials, an average dose of 27±10 IU/kg in PTPs (n=77) and an average dose of 57±20 IU/kg in PUPs (n=17) was given repeatedly at variable intervals longer than 2 weeks. In 64 patients who had both on-demand and prophylactic periods during their time on study, the mean rate of spontaneous musculoskeletal bleeding episodes was less during periods of routine prophylaxis. There were an average of 10 bleeding episodes per year during the prophylactic periods compared to an average of 37 bleeding episodes per year during the on-demand periods. The clinical trial experience with routine prophylaxis in PUPs is limited (n=17). These non-randomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated.

Management of hemostasis was evaluated in the surgical setting where 28 surgical procedures have been performed in 25 patients. The average preoperative dose in PTPs was 59 IU/kg. Procedures included orthopedic procedures, inguinal hernia repair, epidural hematoma evacuation, transposition ulnar nerve, and other minor procedures (e.g., venous access catheter placement and explantation, toenail removal). Circulatory factor VIII levels targeted to restore and maintain hemostasis were achieved. While the one-stage clotting assay was used most frequently in the surgical setting (24 versus 4 surgeries), hemostasis was maintained throughout the surgical period regardless of which assay was used. Hemostatic efficacy was rated as excellent or good in all procedures.

The occurrence of neutralizing antibody (inhibitors) is well known in the treatment of patients with hemophilia A ^1,2,3 . Thirty out of 101 PUPs (30%) developed an inhibitor: 16 out of 101 (16%) with a high titer ( ≥ 5 BU) (11 of the 16 patients had peak values ≥ 10 BU/mL) and 14 out of 101(14%) with a low titer (< 5 BU). In this study the incidence of inhibitor development to factor VIII using ReFacto is similar to that reported for other factor VIII products ^1,2,3,5 .

One of 113 PTPs (0.9%) developed a low titer inhibitor after 107 exposure days with ReFacto. In this study the incidence of inhibitor development to factor VIII using ReFacto is similar to that reported for other factor VIII products ⁴ .