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. 2024 Oct:242:109118.
doi: 10.1016/j.thromres.2024.109118. Epub 2024 Aug 14.

Can edoxaban be used at extremes of bodyweight and in patients with a creatinine clearance ≥95 ml/min? - A population pharmacokinetic analysis

Rachel E Clapham  1 , Victoria Speed  2 , Rosalind Byrne  3 , Lara N Roberts  3 , Julia Czuprynska  3 , Emma Gee  3 , Sinead Duffy  3 , Rachna Patel  3 , Raj K Patel  3 , Roopen Arya  3 , Jignesh P Patel  4
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Free article

Can edoxaban be used at extremes of bodyweight and in patients with a creatinine clearance ≥95 ml/min? - A population pharmacokinetic analysis

Rachel E Clapham et al. Thromb Res. 2024 Oct.
Free article

Abstract

Background: Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin.

Objective: To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics.

Method: Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function.

Results: Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min.

Conclusions: Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.

Keywords: Bodyweight; Direct oral anticoagulant; Edoxaban; Pharmacokinetics; Renal function.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rachel E. Clapham reports financial support was provided by National Institute for Health Research. Victoria Speed reports a relationship with Bayer that includes: speaking and lecture fees. Lara N. Roberts reports a relationship with Chugai that includes: speaking and lecture fees. Lara N. Roberts reports a relationship with Hemab that includes: consulting or advisory. Emma Gee reports a relationship with Sanofi that includes: speaking and lecture fees. Emma Gee reports a relationship with Cardinal Health that includes: speaking and lecture fees. Emma Gee reports a relationship with Bayer that includes: speaking and lecture fees. Sinead Duffy reports a relationship with Cardinal Health that includes: speaking and lecture fees. Roopen Arya reports a relationship with Sanofi that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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