Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa)

Background: Recombinant activated factor VIIa (rFVIIa) is used to treat bleeds in hemophilia patients with inhibitors. A subcutaneous formulation could potentially improve its half‐life and make it suitable for prophylactic treatment. Objectives: A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability). Patients/Methods: This was a multicenter, open‐label, cross‐over comparison of single doses of intravenous rFVIIa 90 μg kg−1and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360 μg kg−1. Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled. Results: Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (Cmax, 0.44–5.16 IU mL−1[across doses]; t1/2, 12.4 h; tmax, 5.6 h) compared with intravenously administered rFVIIa (Cmax, 51.7 IU mL−1; t1/2, 2.7 h; tmax, < 10 min). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1 to 30.1% across dose levels. Dose proportionality was observed within a 2‐fold dose increase but not across the full dose range. No thromboembolic events, drug‐related serious adverse events, severe injection‐site reactions or neutralizing antibodies were reported (primary endpoint). Mild and moderate injection‐site reactions were more frequent with subcutaneous than with intravenous injections. Conclusion: This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.