Stability, efficacy, and safety of continuously infused sucrose‐formulated recombinant factor VIII (rFVIII‐FS) during surgery in patients with severe haemophilia

Abstract

Bolus injection (BI) of sucrose-formulated recombinant factor VIII (rFVIII-FS) is an approved treatment for haemophilia patients undergoing major surgery. Continuous infusion (CI) during surgery has potential benefits by providing steady administration of replacement factor to the patient, avoiding high peaks and low troughs. We tested the stability of rFVIII-FS under CI conditions and conducted a single-centre, open-label, phase III study to evaluate the efficacy and safety of CI using rFVIII-FS in haemophilia A patients undergoing surgery. Patients received bolus rFVIII-FS to achieve >or=80% FVIII levels 30-60 min presurgery, followed by CI of rFVIII-FS at a rate calculated to maintain haemostatic factor levels until days 8-10 post surgery. The rate of infusion was adjusted according to daily calculations derived from the actual clearance. The stability of rFVIII-FS was found to be appropriate for CI for 7 days under the same conditions as clinical settings. Fourteen patients (mean age 37.8 years) receiving on-demand FVIII treatment without a history of inhibitors underwent 15 surgical procedures including joint replacements, synovectomies, multiple tooth extractions, and cholecystectomy. Bleeding was similar to that observed in non-haemophilia patients undergoing similar operations in the same department. Haemostasis during surgery was considered by the attending surgeons as 'excellent' or 'good' in all cases; study investigators rated all 15 cases as 'excellent' overall. There were no adverse events, including inhibitor formation, related to rFVIII-FS. rFVIII-FS was found to be suitable for use in CI in haemophilia A patients undergoing major surgery.

Allometry of Factor VIII and Informed Scaling of Next-Generation Therapeutic Proteins

“…The complete set of collected data is summarized in Table 1. A total of 60 publications were included representing mice, dogs, and humans with HA as well as normal mice, rats, rabbits, and monkeys 7–11,14–16,25–76. A summary of the NCA derived PK parameters CL, V ss , MRT, and half‐life ( t 1/2 ) are presented in Table 2.…”

Continuous infusion during total joint arthroplasty in Japanese haemophilia A patients: comparison study among two recombinants and one plasma‐derived factor VIII

“…Martinowitz et al. [4] reported that continuous infusion of sucrose‐formulated recombinant FVIII is stable, effective and safe during major surgery within 24 h. Lee et al. [3] described that continuous infusion was a cost‐effective delivery system with the portable minipumps, as approximately 30% of the total consumption of the concentrate can be saved, when compared with intermittent bolus infusion.…”

“…Also, many clinical success results were reported using continuous infusion [1–5]. In those reports, the continuous infusion speed was from 2.0 to 6.0 IU kg −1 h −1 when the desired factor level was aimed at 1.0 IU mL −1 .…”

Continuous Infusion of Coagulation Products in Hemophilia

“…Such minor amounts of heparin neither influence the stability of the reconstituted FVIII and FIX [1,25] nor affect in-vivo hemostasis achieved by CI. In some products, addition of heparin may even improve stability, as in the case of rFVIII-FS [16]. In contrast, the addition of unfractionated heparin (UH) to rFVIIa leads to rarely, short-and/or long-term prophylaxis.…”

“…From[16]. Mean per cent recovery ±SD for rFVIII-FS activity based on activity from the time zero level following reconstitution of the concentrate.…”