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

Hannover Medical School, Hannover, Germany.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 06/2011; 9(6):1191-9. DOI: 10.1111/j.1538-7836.2011.04293.x
Source: PubMed


 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.
 A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability).
 This was a multicenter, open-label, cross-over comparison of single doses of intravenous rFVIIa 90μgkg(-1) and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360μgkg(-1) . Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled.
 Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (C(max) , 0.44-5.16IU mL(-1) [across doses]; t(1/2) , 12.4h; t(max) , 5.6h) compared with intravenously administered rFVIIa (C(max) , 51.7IUmL(-1) ; t(1/2) , 2.7h; t(max) , <10min). 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.
 This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.

Download full-text


Available from: Charles R Hay, Oct 20, 2014
  • Source
    • "rFVIIa was first administered at 1 hr before the operation, after which it was administered every 4 hr at a dose of 15.30 µg/kg for 48 hr postoperatively; thereafter the dosing interval was adjusted according to the FVII activity and the patient's progress. FVII activity was measured at baseline and before and 30 min after the intravenous administration of rFVIIa [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital factor VII (FVII) deficiency is a rare hemorrhagic disorder that can cause excessive bleeding during and after surgery in affected patients. The recombinant form of activated factor VII (rFVIIa, NovoSeven® from Novo Nordisk, Bagsvaerd, Denmark), which was developed as a second-generation bypassing agent, has recently been used in the management of bleeding for patients with congenital FVII deficiency. We reviewed the results of 8 surgical procedures in 5 patients with congenital FVII deficiency at the Kyung Hee University Hospital, Gangdong, Seoul, Korea, between January 2008 and June 2010. We administrated rFVIIa preoperatively in six patients and postoperatively in five patients. Between January 2008 and June 2010 at our center, 8 operations were performed successfully and no complications were observed in the 5 patients with congenital FVII deficiency. The median level of FVII activity was 2% (range, 0.6-7%). Four orthopedic procedures, 1 tonsillectomy, and 3 dental extractions were performed. The median duration of hospitalization was 8.5 days (range, 0-15 days). rFVIIa was administered at all procedures, except the dental extraction that was performed using only antifibrinolytic agents without any replacement. No bleeding or thrombogenic complications were observed in any case. Patients with congenital FVII deficiency who require surgery can be treated efficiently and safely with rFVIIa or antifibrinolytic agents. rFVIIa was well tolerated and maintained effective hemostasis and showed good clinical outcome after the major surgery.
    Full-text · Article · Dec 2012 · The Korean journal of hematology

  • No preview · Article · Oct 2012 · Transfusion
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited coagulation disorders constitute a broad spectrum of coagulation factor deficiencies that include X-linked factor (F)VIII or FIX deficiency that causes haemophilia, and autosomal recessive disorders producing heterogeneous deficiencies in fibrinogen (FI), prothrombin (FII), FV, FVII, FX, FXI, FXIII and combined FV+FVIII. Significant advances in treatments for patients with congenital haemophilia A (FVIII deficiency) and B (FIX deficiency) over the last two decades have resulted from improvements in the production, availability and patient access to factor replacement products. Translation of advances in biotechnology, namely recombinant protein technology, targeted protein modifications to improve function and potentially reduce immunogenicity, and advanced formulations to optimize bioavailability and sustain activity offer promisingly new treatments for haemophilia as well as recessively inherited bleeding disorders in patients who otherwise have few therapeutic options. Though a theoretical risk remains for blood-borne viral infections with pooled plasma-derived products, this concern has diminished with breakthroughs in purification and viral inactivation methods. Development of inhibitory antibodies is still the most daunting problem for patients with inherited bleeding disorders, complicating treatment approaches to control and prevent bleeding, and posing risks for allergic and anaphylactic reactions in susceptible patients. The objectives of this review are to (i) highlight emerging advances in hemostatic therapies that are bioengineered to improve pharmacokinetic properties and bioavailability, sustain functional activity, and possibly eliminate immunogenicity of recombinant factor proteins; and (ii) present an overview of key clinical trials of novel factor products currently in the development pipeline.
    No preview · Article · Apr 2013 · Haemophilia
Show more