1.
The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose recombinant activated factor VII in patients with haemophilia A or B
Fernandez-Bello I, Stenmo C, Butta N, Lind V, Ezban M, Jimenez-Yuste V
Haemophilia : the Official Journal of the World Federation of Hemophilia. 2017;23((6):):868-876
Abstract
Monitoring recombinant activated factor VII (rFVIIa) treatment outcomes remains challenging. Thromboelastography (TEG) and the thrombin generation assay (TGA), measure coagulation dynamics over time and are being assessed as potential methods for evaluating and monitoring haemophilia treatment. Lack of standardized TEG/TGA methods makes it difficult to compare results and to establish a correlation with clinical outcomes. AIMS To compare the pharmacokinetics (PK) of rFVIIa after 3x90 mug kg-1 doses vs a single dose (270 mug kg-1 ) in haemophilia patients and to evaluate TEG/TGA results postdosing to determine how these assays relate to PK findings. METHODS Patients in this open-label, single-centre, randomized, crossover trial received one injection of 270 mug kg-1 rFVIIa crossed over with three injections of 90 mug kg-1 rFVIIa in a non-bleeding state. For TEG, kaolin and tissue factor were used as activators; TGA was performed on frozen platelet-rich and platelet-poor plasma, with and without corn trypsin inhibitor. FVIIa activity was evaluated using in vivo samples. RESULTS TGA showed a dose-dependent effect of rFVIIa on thrombin generation; TEG revealed lower dose-dependent effects. Both showed some differences between single-/multiple-dose rFVIIa; both supported the PK findings. CONCLUSION While TEG and TGA are not yet clinically predictive, both supported the PK results. Data suggest that, while a single dose of 270 mug kg-1 rFVIIa provides slightly higher haemostatic potential than the multiple-dose regimen of 3x90 mug kg-1 , the latter results in prolonged activity levels compared with a higher single dose.
2.
Spanish consensus guidelines on prophylaxis with bypassing agents for surgery in patients with haemophilia and inhibitors
Mingot-Castellano ME, Alvarez-Roman MT, Lopez-Fernandez MF, Roca CA, Hirnyk MI, Jimenez-Yuste V, Haro AR, Perez-Garrido R, Sedano Balbas C
European Journal of Haematology. 2016;96((5)):461-74.
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Abstract
INTRODUCTION Patients with severe haemophilia and inhibitors against factor VIII who require surgery need a prophylactic approach to prevent bleeding complications. Scientific evidence to decide the best prophylactic treatment is very limited and mainly based on retrospective or case series. AIMS To develop evidence- and expert opinion-based guidelines for prophylactic therapy for patients with haemophilia and inhibitors undergoing surgery. METHODS A panel of nine Spanish haematologists undertook a systematic review of the literature and selected publications providing relevant information regarding the prophylactic management of patients with haemophilia and inhibitors undergoing dental extraction, minor surgery or major surgery. RESULTS Although evidence is very limited, the panel considers that it seems advisable that prophylaxis should be given in most cases with a bypassing agent (aPCC or rFVIIa) and should start immediately before minor or major surgery. Patients should be closely monitored to enable dose/product modification as needed. CONCLUSION It is necessary to communicate clinical experience in a detailed way in order to ensure optimal schemes of prophylaxis for patients with haemophilia and inhibitors. Development of objective outcomes to evaluate efficacy are crucial. This article is protected by copyright. All rights reserved.
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Cost-effectiveness of recombinant activated factor VII vs. plasma-derived activated prothrombin complex concentrate in the treatment of mild-to-moderate bleeding episodes in patients with severe haemophilia A and inhibitors in Spain
Jimenez-Yuste V, Nunez R, Romero JA, Montoro B, Espinos B
Haemophilia. 2013;19((6):):841-6.
Abstract
Several analyses have shown that recombinant activated factor VII (rFVIIa) is a cost-effective intervention compared with plasma-derived activated prothrombin complex concentrate (pd-aPCC) for the on-demand treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. The aim of the study was to assess the cost-effectiveness of rFVIIa vs. pd-aPCC in the treatment of bleeding episodes in severe haemophilia A patients with inhibitors in Spain. A decision analytic model was designed to evaluate the costs and clinical outcomes of using rFVIIa or pd-aPCC to treat mild-to-moderate joint bleeds in children (<=14 years old) and adults with inhibitors. Data were obtained from a published meta-analysis and a panel of haemophilia experts. The analysis was conducted from the perspective of the Spanish National Healthcare System. One-way sensitivity analyses were performed to assess the impact of model assumptions on study results. In the Treur meta-analysis, rFVIIa resulted in cumulative joint bleed resolution of 88% and 95% after 24 and 36 h, respectively, compared with 62% and 76%, respectively, with pd-aPCC (Treur et al. Haemophilia 2009; 15: 420-36). Here, the mean cost per bleed was estimated at 8473 and 15 579 in children and adults treated with rFVIIa, vs. 8627 and 15 677 in children and adults treated with pd-aPCC. rFVIIa treatment was found to be the dominating option (cheaper and more effective). The one-way sensitivity analysis also confirmed that rFVIIa was less costly than pd-aPCC. The model suggests that rFVIIa is a cost-effective option compared with pd-aPCC for the treatment of mild-to-moderate bleeding episodes in a Spanish setting. 2013 John Wiley & Sons Ltd.
4.
Pharmacokinetic properties of two different recombinant activated factor VII formulations
Morfini M, Jimenez-Yuste V, Eichler H, Fischer R, Kirchmaier CM, Scharling B, Bjerre J
Haemophilia. 2012;18((3):):431-6.
Abstract
Recombinant factor VIIa is indicated for treatment of bleeding episodes in patients with haemophilia A or B with inhibitors; in FVII deficiency and in Glanzmann's thrombasthenia. The aim of the study reported here was to compare the pharmacokinetic profiles between two formulations of rFVIIa that are produced in two different cell lines and media: Chinese hamster ovary cells cultured in a serum-free medium (CHO-rFVIIa) and baby hamster kidney cells cultured in a non-human serum-based medium (BHK-rFVIIa). Two clinical trials were performed; one in healthy subjects and the other in patients with congenital haemophilia A or B, with or without inhibitors. Subjects were recruited into a two-way crossover trial and were randomized to receive a dose of CHO-rFVIIa and BHK-rFVIIa. Healthy subjects received one dose of 90 ug CHO-rFVIIa kg(-1) bodyweight (bw) in the newly developed room-temperature stable rFVIIa formulation and one dose of 90 ug BHK-rFVIIa kg(-1) bw, in the original rFVIIa formulation. Patients with haemophilia received one dose of 270 ug CHO-rFVIIa kg(-1) and one dose of 270 ug BHK-rFVIIa kg(-1), both in the room-temperature stable formulation. The trials showed higher FVII activity levels [higher area under the plasma concentration-time curve (AUC)] following administration of CHO-rFVIIa than after BHK-rFVIIa. Therefore, bioequivalence could not be established. The difference in FVII activity levels is believed to be a result of different glycosylation patterns between the two products. Neither the use of CHO-rFVIIa nor the use of one single dose of 270 ug kg(-1) of the newly developed room-temperature stable rFVIIa raised any safety concerns. 2011 Blackwell Publishing Ltd.