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

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2025-06-05 DOI:10.1007/s40262-025-01534-z

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

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引用次数: 0

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 (V_d/F) of 23.7 L, and an absorption rate constant (k_a) of 0.652/h. Interindividual variability (IIV) was observed in CL/F but not in V_d/F and k_a. 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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胺碘酮对心脏手术后患者阿哌沙班暴露的影响——人群药代动力学研究。

目的：探讨胺碘酮对心脏手术后心房颤动患者阿哌沙班药代动力学的影响。方法：采用液相色谱-串联质谱法（LC-MS/MS）定量分析心脏手术术后接受或未接受胺碘酮治疗患者的阿哌沙班浓度。在NONMEM®7.5中使用非线性混合效应建模，采用一阶条件估计与相互作用建立群体药代动力学模型。使用Simulx®（Lixoft）分析了不同给药方案下胺碘酮和肌酐清除率（CrCL）对阿哌沙班暴露的影响。结果：共纳入76种阿哌沙班浓度的33例患者。阿哌沙班的清除率（CL/F）为3.05 L/h，表观分布容积（Vd/F）为23.7 L，吸收速率常数（ka）为0.652/h，单室模型最能描述阿哌沙班的药代动力学。在CL/F中观察到个体间变异（iv），但在Vd/F和ka中没有观察到。协变量胺碘酮和CrCL与阿哌沙班CL/F独立相关。在胺碘酮联合治疗下，模拟预测阿哌沙班面积在浓度-时间曲线（AUC）下增加44-49%，当CrCL为35 mL/min时，AUC几乎翻了一番。在胺碘酮治疗的CrCL范围为15- 50ml /min时，每日两次的2.5 mg阿哌沙班剂量被确定为一种潜在的给药选择。结论：联合胺碘酮治疗降低了阿哌沙班CL/F，并增加了肾功能受损患者高暴露的风险。在联合胺碘酮治疗下，CrCL范围为30-50 mL/min时，每日服用2.5 mg阿哌沙班被确定为一种新的给药选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.