An anticoagulant that does not cause bleeding – an abrupt stop on the road to the Holy Grail

Meijers, Joost C. M.

doi:10.1111/jth.14638

Cited by 2 publications

(2 citation statements)

References 17 publications

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“…Additional analyses are therefore necessary to complete this pilot study with a large cohort of patients experiencing drug interactions with edoxaban. These limitations highlighted in this study with edoxaban should also be assessed for FIIa inhibitors (currently only dabigatran is marketed) 43 …”

Section: Discussionmentioning

confidence: 99%

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Siriez

Yıldız

Bouvy³

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Introduction:Edoxaban is the only anti-Xa inhibitor metabolized in pharmacologically active moiety that could interfere with chromogenic anti-Xa assays, especially in case of drug-drug interactions or physiological disorders. Materials and methods:We evaluated the contribution of the main metabolite of edoxaban, edoxaban-M4 (M4), in 79 plasma samples from patients taking edoxaban.The total anti-Xa activity was evaluated on three different chromogenic factor Xabased assays. Results were compared with a validated ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry measurement. Edoxaban and its active M4 metabolite have also been spiked separately in normal pooled plasma to assess the sensitivity of chromogenic anti-Xa assays to both molecules individually.Results: Spiked edoxaban or M4 provided different slopes of linear regression models between chromogenic and chromatographic measurement (from 0.97 for STA Liquid Anti-Xa to 1.10 for Biophen Heparin LRT Low with edoxaban and from 0.70 for Biophen DiXaI High to 0.83 for Biophen Heparin LRT High, respectively). A positive correlation is observed between the increase of the ratio M4/edoxaban with the difference between chromogenic and chromatographic measurements. Conclusion:Edoxaban and M4 do not similarly impact chromogenic assays, leading to biased chromogenic estimations of ponderal concentrations. In patient samples, this impact is even more important at low concentrations or in the case of an increase in the M4/edoxaban ratio because of hepatic or renal impairments or in case of drug interactions. This study highlights the limitations and risks of error of expressing results in ponderal concentrations instead of global activity anti-Xa.

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Section: Discussionmentioning

confidence: 99%

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Siriez

Yıldız

Bouvy³

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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“…Although some reasons for the lack of efficacy in the context of postoperative dosing in total knee replacement patients have been posited, for example, weak thrombin inhibition or inability of JNJ‐9375 to attenuate the growth of thrombin that formed before drug administration (Meijers & Middeldorp, 2019; Weitz et al, 2019), investigation of this compound within other clinical contexts (e.g. preoperative initiation of dosing or prevention of medical device thrombosis) remains feasible (Meijers & Middeldorp, 2019). Hence, establishment of rapid and effective reversal of JNJ‐9375 activity is medically necessary in situations of bleeding emergency.…”

Section: Discussionmentioning

confidence: 99%

Translational PK/PD and model‐informed development of JNJ‐67842125, a F_ab reversal agent for JNJ‐64179375, a long‐acting thrombin inhibitor

Ayyar

Jaiprasart

Geist

et al. 2021

British J Pharmacology

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Background and Purpose Antigen‐binding fragment (Fab) reversal agents were developed to reverse, in bleeding emergency, the long‐acting anticoagulant effect of JNJ‐64179375 (JNJ‐9375), a monoclonal antibody that binds exosite‐1 on thrombin. Experimental Approach The pharmacokinetic and pharmacodynamic (PK/PD) activities of three reversal agents of varying in vitro binding affinities to JNJ‐9375 were characterised in cynomolgus monkeys. The time course of JNJ‐9375 anticoagulant activity and reversal effects of each agent were evaluated. A mechanism‐based PK/PD model, which integrated free serum concentrations of reversal agent, total and free serum concentrations of JNJ‐9375, and thrombin time, was developed to quantitatively relate JNJ‐9375 neutralisation to reversal of induced thrombin time prolongation. Model‐based allometric scale‐up of the lead reversal agent and the PK/PD relationship of JNJ‐9375 in healthy volunteers were utilised to predict clinical dosing regimens. Key Results Lowering of free JNJ‐9375 by the reversal agents corresponded with reversal of thrombin time prolongation. Total JNJ‐9375 displayed typical mAb clearance at 2.75 ml·day−1·kg−1, whereas reversal agents cleared faster between 1400 and 2400 ml·day−1·kg−1. The model‐estimated in vivo KD values for JNJ‐9375 reversal agents were 9 nM (ICHB‐256), 0.4 nM (ICHB‐281) and 13.7 pM (ICHB‐164), in rank‐ordered agreement of their KD values determined in vitro. The three reversal agents exhibited different neutralisation characteristics in vivo, governed primarily by their binding kinetics to JNJ‐9375. The model predicted a priori free JNJ‐9375 kinetics after dosing ICHB‐164 (JNJ‐67842125) and JNJ‐9375 under a different regimen. Conclusion and Implications The results enabled selection of JNJ‐67842125 as the reversal agent for JNJ‐9375.

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An anticoagulant that does not cause bleeding – an abrupt stop on the road to the Holy Grail

Cited by 2 publications

References 17 publications

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Translational PK/PD and model‐informed development of JNJ‐67842125, a F_ab reversal agent for JNJ‐64179375, a long‐acting thrombin inhibitor

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An anticoagulant that does not cause bleeding – an abrupt stop on the road to the Holy Grail

Cited by 2 publications

References 17 publications

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

The edoxaban‐M4 metabolite and measurement of edoxaban by chromogenic assays in human plasma

Translational PK/PD and model‐informed development of JNJ‐67842125, a Fab reversal agent for JNJ‐64179375, a long‐acting thrombin inhibitor

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Product

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Translational PK/PD and model‐informed development of JNJ‐67842125, a F_ab reversal agent for JNJ‐64179375, a long‐acting thrombin inhibitor