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. 2025 Aug;64(8):1191-1201.
doi: 10.1007/s40262-025-01534-z. Epub 2025 Jun 5.

Effect of Amiodarone on Apixaban Exposure in Patients after Cardiac Surgery-A Population Pharmacokinetic Study

Benedict Morath  1 , Kathrin I Foerster  2 , Ute Chiriac  3 , Marcin Zaradzki  4 , Torsten Hoppe-Tichy  3 , David Schrey  5 , Jürgen Burhenne  2 , David Czock  2 , Matthias Karck  4 , Walter E Haefeli  2 , Sebastian G Wicha  5
Affiliations

Effect of Amiodarone on Apixaban Exposure in Patients after Cardiac Surgery-A Population Pharmacokinetic Study

Benedict Morath et al. Clin Pharmacokinet. 2025 Aug.

Abstract

Aim: To investigate the effect of amiodarone on apixaban pharmacokinetics in cardiac surgery patients with postoperative atrial fibrillation.

Methods: Apixaban concentrations of postoperative cardiac surgery patients with or without amiodarone therapy were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in clinical routine. A population pharmacokinetic model was built using nonlinear mixed effects modeling in NONMEM® 7.5 using first-order conditional estimation with interaction. The impact of amiodarone and creatinine clearance (CrCL) on apixaban exposure under various dosing regimens was analyzed using Simulx® (Lixoft).

Results: A total of 33 patients with 76 apixaban concentrations were included. A one-compartment model best described the pharmacokinetics of apixaban with a clearance (CL/F) of 3.05 L/h, apparent volume of distribution (Vd/F) of 23.7 L, and an absorption rate constant (ka) of 0.652/h. Interindividual variability (IIV) was observed in CL/F but not in Vd/F and ka. The covariates amiodarone and CrCL were independently associated with apixaban CL/F. Under concomitant amiodarone therapy, simulations predicted an increase of 44-49% in apixaban area under the concentration-time curve (AUC), and AUC nearly doubled at CrCL 35 mL/min. A dose of 2.5 mg apixaban twice daily (b.i.d.) was identified as a potential dosing option in the CrCL range of 15-50 mL/min under amiodarone comedication.

Conclusions: Concomitant amiodarone therapy reduced apixaban CL/F and increased the risk of high exposure in patients with impaired renal function. A dose of 2.5 mg apixaban b.i.d. for a CrCL range of 30-50 mL/min under concomitant amiodarone therapy was identified as a new dosing option.

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Conflict of interest statement

Declarations. Competing Interests: The authors declare that they have no competing interests. Contributions: Conceptualization—Benedict Morath, Kathrin I. Foerster, David Czock, Marcin Zaradzki, Matthias Karck, Walter E. Haefeli, and Sebastian G. Wicha; methodology—Benedict Morath, Ute Chiriac, Jürgen Burhenne, and Sebastian G. Wicha; formal analysis and investigation—Benedict Morath, Kathrin I. Foerster, Ute Chiriac, Jürgen Burhenne, Torsten Hoppe-Tichy, David Schrey, and Sebastian G. Wicha; Writing—original draft preparation—Benedict Morath, Ute Chiriac, and Sebastian G. Wicha; writing—review and editing—Benedict Morath, Kathrin I. Foerster, Ute Chiriac, Marcin Zaradzki, Torsten Hoppe-Tichy, David Schrey, Jürgen Burhenne, David Czock, Matthias Karck, Walter E. Haefeli, and Sebastian G. Wicha; resources—Torsten Hoppe-Tichy, Matthias Karck, and Walter E. Haefeli; supervision—Walter E. Haefeli and Sebastian G. Wicha. Financial Interests: The authors declare that they have no financial interests. Funding Statement: No funding was received for this work. Data Availability: Data are available upon reasonable request. Ethics: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. A positive vote of the Ethics Committee of the Medical Faculty of Heidelberg University was obtained before the start of the study (S-523/2021). Consent to Participate: Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Prediction-corrected visual predictive check of the population pharmacokinetic model of apixaban; 10 th to 90 th percentile (dashed lines) and median (solid line) and corresponding 95% confidence intervals of the model prediction. N = 500 simulations
Fig. 2
Fig. 2
Population predictions (PRED, left) or individual predictions (IPRED, right) versus observed apixaban concentration (DV)
Fig. 3
Fig. 3
Time after dose (left) or individual predictions (right) versus normalized prediction distribution error (NPDE). The dashed lines indicate the expected 2.5 th, 50 th, and 97.5 th percentile
Fig. 4
Fig. 4
Covariate relationships of apixaban CL/F versus amiodarone comedication (left) and CrCL (right). Solid line (right): estimated covariate relationship. P-value from comparison of post hoc estimates of CL/F using a two-sided t-test
Fig. 5
Fig. 5
Apixaban Cmin for the labeled doses of 5 mg b.i.d. or 2.5 mg b.i.d. in 1000 simulated individuals with differing CrCL with (blue boxes) or without amiodarone (green boxes). Italic numbers above boxes show the proportion of profiles with Cmin > 230 ng/mL of the respective scenario. Italic numbers below boxes show the proportion of profiles with Cmin < 34 ng/mL. Dashed lines indicate an expected Cmin range of 34–230 ng/mL (5 th, 95 th percentile) [13, 28]. b.i.d. twice daily, Cmin trough concentrations, CrCL creatinine clearance
Fig. 6
Fig. 6
Apixaban Cmin distribution of the labeled dose (green boxes) and a potential dosing strategy for amiodarone comedication (blue boxes) at different CrCL ranges. Italic numbers above boxes show the proportion of profiles with Cmin > 230 ng/mL of the respective scenario. Italic numbers below boxes show the proportion of profiles with Cmin < 34 ng/mL. b.i.d. twice daily, Cmin trough concentrations, CrCL creatinine clearance
Fig. 7
Fig. 7
Predicted apixaban concentrations over 48 h using the available strengths of 2.5 mg and 5 mg b.i.d. (simulated for 1000 individuals). Green shaded plots show the labeled dose. Blue shaded plots show the proposed dosing scheme with amiodarone comedication. Dashed lines represent the 5 th and 95 th percentile; the solid line represents the median. The dotted line indicates the bleeding threshold of Cmin: 230 ng/mL apixaban [18, 27]. b.i.d. twice daily, CrCL creatinine clearance
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