Comparison of coagulant activity of factor VII and activated factor VII activity assays when used for determination of recombinant activated factor VII levels in plasma

Scharling, B.; Nielsen, Gert; Klitgaard, Thomas; Skovsted, Thor Aa; Møss, Judi; Segel, Stine; Larsen, L. F.

doi:10.1097/mbc.0b013e3282e7febb

Cited by 12 publications

(11 citation statements)

References 12 publications

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“…Plasma samples were mixed with FVII‐deficient plasma, and coagulation was initiated by the addition of a truncated recombinant soluble tissue factor (rsTF). The rsTF‐FVIIa complex is biologically active and can activate coagulation factor X, but it is not capable of activating rsTF‐bound FVII to rsTF‐FVIIa [16].…”

Section: Methodsmentioning

confidence: 99%

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

Tiede

Friedrich

Stenmo

et al. 2011

Journal of Thrombosis and Haemostasis

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of subcutaneously administered recombinant activated factor VII (rFVIIa). J Thromb Haemost 2011; 9: 1191-9.Summary. 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). . 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 (C max , 0.44-5.16 IU mL )1 [across doses]; t 1/2 , 12.4 h; t max , 5.6 h) compared with intravenously administered rFVIIa (C max , 51.7 IU mL )1; t 1/2 , 2.7 h; t max , < 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.

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Section: Methodsmentioning

confidence: 99%

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

Tiede

Friedrich

Stenmo

et al. 2011

Journal of Thrombosis and Haemostasis

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“…N7‐GP in plasma was measured by a modified coagulation bioassay (FVIIa activity with the Staclot VIIa‐rTF assay; Diagnostica Stago). The Staclot VIIa‐rTF assay was applied with minor modifications: a Pipes buffer containing 0.1% bovine serum albumin was used to dilute plasma samples, controls, and calibrator [21]. rFVIIa was diluted to a final concentration of 300 mIU mL −1 and calibrated against the international FVIIa standard (89/688; International Institute of Biological Standards and Controls, UK).…”

Section: Subjectsmentioning

confidence: 99%

Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects

Møss

Rosholm

Laurén

2011

Journal of Thrombosis and Haemostasis

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To cite this article: Møss J, Rosholm A, Lauré n A. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost 2011; 9: 1368-74.Summary. Background: Extensive research is currently ongoing to prolong the half-life of coagulation factors. One of these techniques is glycoPEGylation, which has also been applied to recombinant activated factor VII (rFVIIa), resulting in a rFVIIa derivative (N7-GP) with a prolonged terminal half-life (t 1/2 ). The main clinical purpose of N7-GP is to provide safe and effective prophylaxis to patients with hemophilia and inhibitors. The prolonged t 1/2 of N7-GP can potentially reduce the dosing frequency and thereby facilitate convenience and compliance, which are two significant barriers to effective prophylaxis. Objectives: To determine the safety and pharmacokinetics of single doses of N7-GP in healthy men. Methods: A randomized, placebo-controlled, dose-escalation trial with five cohorts (N7-GP dose of 12.5-100 lg kg )1 ) was performed. In each cohort, eight subjects were randomized to receive N7-GP (n = 6) or placebo (n = 2). Results: The mean FVIIa activity was measurable for up to at least 72 h after dosing, and the overall mean t 1/2 for FVIIa activity was 15 h. The pharmacokinetics of N7-GP appeared to be dose-proportional in the dose range investigated. No serious adverse events (including thromboembolic events) were reported. The frequency of adverse events was similar in both the placebo and N7-GP groups. No neutralizing antibodies against N7-GP were detected. A pharmacologic effect was apparent from a dose-dependent statistically significant decrease in the mean prothrombin time in all N7-GP groups as compared with placebo. Conclusions: N7-GP had a plasma half-life of 15 h and a profile that makes it a potential candidate for prophylaxis in patients with hemophilia and inhibitors.

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“…Novoseven is a safe and effective drug in the treatment of inherited FVII deficiency and is becoming the first choice of products to treat the disease. To improve rFVIIa physical stability, a new formulation stable up to 25°C has been tested in a randomized, double-blind trial that has assessed equivalence with the classic formulation concerning safety, efficacy and pharmacokinetic parameters [30], even though differences exist in the determination of rFVIIa plasma levels, especially very low levels, when different assays are used [31].…”

Section: Disease Managementmentioning

confidence: 99%

Factor VII deficiency: defining the clinical picture and optimizing therapeutic options

Lapecorella¹,

Mariani²

2008

Haemophilia

110

100

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Summary. Factor VII (FVII) deficiency is the most frequent among rare congenital bleeding disorders, accounting for one symptomatic individual per 500 000 population, apparently without any racial/ ethnic predilection. FVII deficiency prevalence in the general population is probably higher because of the presence of asymptomatic and poorly symptomatic individuals. In accordance with the role of FVII as part of the initiating complex of the extrinsic coagulation pathway, laboratory diagnosis is easy, because FVII deficiency is the only congenital bleeding disorder characterized by isolated prolonged prothrombin time. Molecular diagnosis is available, and a broad spectrum of mutations has been characterized in the FVII gene, which is located in chromosome 13. Clinical manifestations are heterogeneous, ranging from severe life-threatening haemorrhages, such as cerebral, gastrointestinal, and joint haemorrhages, to miscellaneous minor bleeding. The main clinical features in our database (International Registry on Congenital FVII Deficiency database, n = 515) are as follows: (i) the absence of a clear-cut and consistent correlation between bleeding symptoms and FVII clotting levels; (ii) an excess of symptomatic women compared with men; (iii) frequent surgery-related bleeding, which is often a diagnostic tool in previously asymptomatic individuals. Several therapeutic options are possible, including plasma-derived and recombinant products, but therapeutic schedules, optimal dosages, and administration times still have to be precisely defined, and clinical studies, including online registries such as the Seven Treatment Evaluation Registry, are actually ongoing to achieve in a better manner a safe, rational and standardized substitution treatment for this congenital disorder.

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Comparison of coagulant activity of factor VII and activated factor VII activity assays when used for determination of recombinant activated factor VII levels in plasma

Cited by 12 publications

References 12 publications

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

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

Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects

Factor VII deficiency: defining the clinical picture and optimizing therapeutic options

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