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

Tiede, Andreas; Friedrich, Ute; Stenmo, C.; Allen, Geoffrey; Giangrande, Paul; Goudemand, Jenny; Hay, Colin W.; Holmström, Margareta; Klamroth, Robert; Lethagen, Stefan; McKenzie, Steven E.; Miesbach, Wolfgang; Négrier, Claude; Yuste, Vı́ctor J.; Berntorp, Erik

doi:10.1111/j.1538-7836.2011.04293.x

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…Available data suggest that single‐dose rFVIIa is at least as effective as the multiple‐dose regimen while offering easier administration, improved treatment compliance, less injection‐related pain and faster bleed control . Our PK data, based on FVIIa activity and FVII antigen assessments, were similar between the two regimens and consistent with previous studies evaluating rFVIIa PK . As expected, there was a build‐up of FVIIa activity following repeated rFVIIa doses and the accumulation ratio of 1.8 supports the increased efficacy provided by additional doses following the first dose of 90 μg kg −1 .…”

Section: Discussionsupporting

confidence: 87%

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The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

Bello¹,

Stenmo

Butta³

et al. 2017

Haemophilia

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Section: Discussionsupporting

confidence: 87%

“…PK profiles and parameters ( Figure 2; Table 2) were in accordance with previously published PK data for single-dose rFVIIa in haemophilia patients 20,21 and healthy subjects. 22 Figure 2).…”

Section: Pharmacokineticssupporting

confidence: 88%

The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

Bello¹,

Stenmo

Butta³

et al. 2017

Haemophilia

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“…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]. …”

Section: Discussionmentioning

confidence: 99%

Surgery in patients with congenital factor VII deficiency: A single center experience

et al. 2012

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BackgroundCongenital 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.MethodsWe 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.ResultsBetween 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.ConclusionPatients 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.

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“…In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3).…”

Section: Immunogenicity Of Proteins Given Via Sc Routementioning

confidence: 99%

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Fathallah

Bankert

Balu‐Iyer

2013

AAPS J

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Abstract. The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.KEY WORDS: biotechnology; immunogenicity; mitigation of immunogenicity; protein therapeutics; subcutaneous administration. IMMUNOGENICITY OF PROTEINS GIVEN VIA SC ROUTEThe subcutaneous (sc) route of administration of therapeutic proteins is desired over the intravenous (iv) route due to patient comfort and compliance. In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3). As most of the vaccines are given via the sc route, it is expected that the sc route is more immunogenic than the iv route. However, a recent comparative clinical study of sc vs iv administration of abatacept, a fusion protein of Fc of human IgG and extracellular domain of CTLA-4, showed that the efficacy and immunogenicity are comparable between the two routes of administration (4,5). However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7-9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9). Based on clinical experience of head-to-head comparison and a few preclinical studies, one could argue that the generalization that the sc route is more immunogenic than the iv route is not universally valid.A comparative immunogenicity study of three brands of insulin in type 1 diabetics showed an increase in incidence of anti-insulin titer development, across brands, in patients selfadministering via sc route as compared to iv administration in hospital in the same cohort (10). In the therapeutic use of erythropoietin-α, incidence of immunogenicity increased with the change from iv to sc. It is appropriate to mention here that elimination of human serum albumin from the formulation as well as stopper material change (11) coincided with changes in route of administration, and thus, the effect of the sc route of administration on immunogenicity is not unambiguous for erythropoietin. There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar ob...

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

Cited by 17 publications

References 36 publications

The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

Surgery in patients with congenital factor VII deficiency: A single center experience

Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

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