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Clinical Trial
. 2025 Feb;64(2):307-321.
doi: 10.1007/s40262-025-01476-6. Epub 2025 Jan 24.

Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis

Celine Konecki  1 , Mark L Lipman  2 , Thomas A Mavrakanas #  3 , Zoubir Djerada #  4
Affiliations
Clinical Trial

Population Pharmacokinetic Modelling of Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis

Celine Konecki et al. Clin Pharmacokinet. 2025 Feb.

Abstract

Background and objective: Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery.

Methods: Patients received 2.5 mg of apixaban twice daily for 9 days, followed by 5 mg twice daily for 8 days after a 5-day washout period (NCT02672709). Apixaban concentrations were measured on and off dialysis. A population pharmacokinetic model was developed using parametric and non-parametric methods. Simulations were performed to assess plasmatic exposure and the time to reach clinically relevant apixaban concentrations after treatment discontinuation for seven dosing regimens and 13 dialysis schedules.

Results: A total of 289 apixaban concentrations were measured, including 85 during haemodialysis. The best model was a two-compartment model with first-order elimination. Dialytic clearance was estimated at 1.20 L/h with high inter-individual variability. Apixaban daily exposure was proportional to the total daily dose, independent of dosing frequency and dialysis timing. The standard discontinuation period of 48-72 h before surgery was insufficient to achieve clinically negligible concentrations in patients undergoing haemodialysis.

Conclusions: We propose the first pharmacokinetic model to characterise apixaban clearance in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis. Simulations suggest that dialysis timing is not critical for monitoring apixaban, and the discontinuation period before surgery should be extended beyond current recommendations.

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Conflict of interest statement

Declarations. Funding: Prof. Mavrakanas is supported from a Fonds de Recherche Santé Quebec (FRSQ) J1 Clinician Scholar award and a Kidney Research Scientist Core Education and National Training (KRESCENT) program New Investigator Award. Conflicts of Interest/Competing Interests: Celine Konecki, Mark L. Lipman, and Zoubir Djerada have no conflicts of interest that are directly relevant to the content of this article. Prof. Mavrakanas has received speaker honoraria from Bayer, BMS Canada, Janssen, Astra Zeneca, and Pfizer, and has served on advisory boards for Boehringer Ingelheim, Bayer, GSK, and Servier outside the submitted work. He has also received research grants from Astra Zeneca and Pfizer. Ethics Approval: The original study was performed in line with the principles of the Declaration of Helsinki and approval was granted by the Research Ethics Committee of the Jewish General Hospital. Consent to Participate: Participants provided written informed consent. Consent for Publication: Not applicable. Availability of Data and Material: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Code Availability: Not applicable. Authors’ Contributions: CK: conceptualisation, methodology, data curation, formal analysis, investigation, visualisation, writing (original draft). MLL: conceptualisation, methodology, data curation, investigation, resources, writing (review and editing). TAM: conceptualisation, methodology, data curation, investigation, resources, supervision, writing (review and editing). ZD: conceptualisation, methodology, data curation, formal analysis, investigation, supervision, writing (review and editing).

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