Monitoring the bioavailability of FEIBA with a thrombin generation assay

Váradi, Katalin; Négrier, Claude; Berntorp, Erik; Astermark, Jan; Bordet, Jean‐Claude; Morfini, Massimo; Linari, Silvia; Schwarz, HP; Turecek, P. L.

doi:10.1046/j.1538-7836.2003.00450.x

Cited by 141 publications

(150 citation statements)

References 16 publications

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“…This linear PK profile enables accurate prediction of plasma ACE910 concentration according to dose. Notably, the mean half-life of ACE910 ranged between 28.3 and 34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours 1 ; rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [TG-based half-life] 13 ) and drugs recently approved or under development (#19 hours). 5,[21][22][23][24] Concizumab is a humanized anti-tissue factor pathway inhibitor antibody and is also subcutaneously available in humans.…”

Section: Discussionmentioning

confidence: 99%

“…1 Patients who develop FVIII inhibitors are treated with bypassing agents, including recombinant activated factor VII (rFVIIa) 7 or activated prothrombin complex concentrate (aPCC). 8 Frequent intravenous administration of these agents is required because of their unstable hemostatic efficacy caused by short half-lives (rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [thrombin generation (TG)-based half-life] 13 ). New treatments with more convenient administration routes, lower administration frequency, and less immunogenicity against coagulation factors are needed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

Uchida

Sambe

Yoneyama³

et al. 2016

Blood

218

225

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Key Points• Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 5 weeks, and FVIII-mimetic procoagulant activity in humans.• ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and white adults.ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n 5 6 per dose group) or placebo (n 5 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIIIneutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (antidrug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

Uchida

Sambe

Yoneyama³

et al. 2016

Blood

218

225

View full text Add to dashboard Cite

show abstract

“…This expectation appears justified, as the thrombin generation test has since improved significantly by the introduction of continuous techniques employing chromogenic and fluorogenic substrates [7][8][9][10], thus replacing the original subsampling techniques which are laborious and time consuming. Simultaneous handling of many samples is possible by this method, thus saving time and costs.…”

Section: Introductionmentioning

confidence: 99%

“…Fluorescence based applications have now the widest distribution because these techniques have advantages over the absorption based approaches as the signal in the latter is disturbed by turbidity caused by coagulation events. It is now possible to perform measurements for the characterization of hereditary or acquired coagulation disturbances as well as for investigations into the influence of various medicines that affect the coagulation process beyond the time of clotting [9][10][11][12][13][14][15][16][17][18][19]. Hemker et al have reviewed further literature on such applications [20].…”

Section: Introductionmentioning

confidence: 99%

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Tapp¹,

Grundmann²,

Kusch³

et al. 2009

TOATHERTJ

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Abstract:The technique of thrombin generation has been established as a promising tool for the diagnosis, risk estimation, and perhaps prognosis of coagulation insufficiencies. Without further experimentation an indication can be obtained if a sample donor carries the risk for haemophilia or thrombophilia, either congenital or acquired. A comparison of two different thrombin generation assays is presented, demonstrating that a currently not commercially available test allows an easier and cheaper calibration than its commercial counterpart. This is achieved by employment of a less efficient but highly specific peptide substrate for thrombin and the involvement of low amounts of analyte (plasma samples).

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“…faktor készítményekkel történő terápia monitorozására és a szükséges dózis meghatározására [44]. A TG-vel, mint globális teszttel, vizsgálható az inhibitorképződés esetén alkalmazott speciális, úgynevezett inhibi tor bypassing terápia hatásossága [45,46]. A TG-mérés alkalmas fokozott vérzéskockázat esetén a betegek perioperatív monitorozására.…”

Section: Vérzéshajlammal Járó Betegségekkel Kapcsolatos Vizsgálatokunclassified

Thrombin generation assays and their clinical application

2014

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A trombin a véralvadási kaszkád egyik kulcsenzime, amely mind pro-, mind antikoaguláns funkcióval rendelkezik. Központi szerepe folytán a trombin képződése a véralvadási folyamat egyik legfontosabb lépése, amely az úgynevezett trombingenerációs vizsgálattal jellemezhető. A trombingeneráció globális véralvadási teszt, amely átfogó képet ad a haemostasis állapotáról. Karakterisztikáját egyaránt befolyásolják a pro-és az antikoaguláns folyamatok, ezáltal alkalmas a fokozott trombóziskészség és a vérzékenység kimutatására is. Klinikai vizsgálatok igazolják a trombingeneráció fokozódását vénás és artériás trombózishajlam esetében. Segíthet az antikoaguláns terápia monitorozásában, faktorinhibitorokkal történő antikoaguláns kezelés esetében is. A trombingenerációs vizsgálatok eredményei hemofília esetén jól tükrözik a vérzés súlyosságát, és monitorozható a faktorkészítményekkel történő terápia. Információt adhat azokban az esetekben is, amikor a hemofíliás betegnél inhibitorok jelennek meg, és emiatt speciális kezelésre van szükség. A klinikai gyakorlatban történő alkalmazáshoz elengedhetetlen a módszer standardizálása és a klinikai dön-téshozatalhoz szükséges küszöbértékek meghatározása. Orv. Hetil., 2014, 155(22), 851-857. Kulcsszavak: véralvadási vizsgálatok, trombózis, vérzékenység, trombin Thrombin generation assays and their clinical applicationThrombin is a key enzyme of the coagulation system, having both pro-and anticoagulant functions. Thus, the generation of thrombin is one of the most important steps in coagulation. Global haemostasis assay, the so-called thrombin generation test is appropriate for its assessment. Since thrombin generation is sensible for both pro-and anticoagulant processes it can be applied for the general characterisation of the risk of thrombosis and bleeding, too. Clinical studies confi rmed augmented thrombin generation in patients with high risk of venous or arterial thrombosis. Anticoagulant therapy (also novel oral anticoagulant treatment) can be monitored by thrombin generation. In case of haemophilia thrombin generation assays refl ect bleeding severity. It is applicable for monitoring of both conventional haemophilia treatment and inhibitor-bypassing therapy, which is needed when inhibitors develop in patients. Standardization of thrombin generation methods and determination of cut off values are required before its application in clinical practice.

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Monitoring the bioavailability of FEIBA with a thrombin generation assay

Abstract: This assay enables the pharmacodynamic and pharmacokinetic properties of bypassing therapies to be monitored, thus helping to optimize treatment.

Cited by 141 publications

References 16 publications

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

Thrombin generation assays and their clinical application

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