P-糖蛋白抑制剂他莫昔芬对乳腺癌女性中依度沙班的血浆水平的影响。

Effect of the P-glycoprotein inhibitor tamoxifen on edoxaban plasma levels in women with breast cancer.

机构信息

Department of Internal Medicine, Tergooi Medical Center, Hilversum, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, the Netherlands.

出版信息

Thromb Res. 2023 Aug;228:46-53. doi: 10.1016/j.thromres.2023.05.021. Epub 2023 May 29.

DOI:10.1016/j.thromres.2023.05.021

PMID:37269716

Abstract

BACKGROUND

Concomitant use of P-glycoprotein inhibitors can reduce clearance of edoxaban and increase its plasma concentration. Caution is advised with simultaneous use of edoxaban and the frequently used P-glycoprotein inhibitor tamoxifen. However, pharmacokinetic data are lacking.

OBJECTIVES

This study aimed to assess the effect of tamoxifen on edoxaban clearance.

METHODS

This was a prospective, self-controlled, pharmacokinetic study in breast cancer participants starting tamoxifen. Edoxaban was given at a dose of 60 mg once daily for 4 consecutive days, first without tamoxifen and later with concomitant tamoxifen in steady-state. On day 4 of both edoxaban sequences, serial blood samples were taken. A population pharmacokinetic model was developed using nonlinear mixed effects modelling in which the effect of tamoxifen on edoxaban clearance was assessed. Additionally, mean area under the curves (AUC) were estimated. Geometric least square means (GLM) ratios were calculated and no interaction was concluded if the 90 % CI was within the 80-125 % no-effect boundaries.

RESULTS

Twenty-four women with breast cancer scheduled for tamoxifen were included. The median age was 56 years (IQR 51-63). The average edoxaban clearance was 32.0 L/h (95 % CI, 11.1-35.0 L/h). There was no effect of tamoxifen on edoxaban clearance, with a fraction of 100 % (95 % CI 92-108) compared to clearance without tamoxifen. The mean AUCs were 1923 ngh/ml (SD 695) without tamoxifen and 1947 ngh/ml (SD 595) with tamoxifen (GLM-ratio 100.4; 90 % CI 98.6-102.2).

CONCLUSIONS

Concomitant use of the P-glycoprotein inhibitor tamoxifen does not lead to reduced clearance of edoxaban in patients with breast cancer.

摘要

背景

P-糖蛋白抑制剂的同时使用会降低依度沙班的清除率并增加其血浆浓度。因此，在同时使用依度沙班和常用的 P-糖蛋白抑制剂他莫昔芬时应谨慎。然而，目前缺乏药代动力学数据。

目的

本研究旨在评估他莫昔芬对依度沙班清除率的影响。

方法

这是一项在开始使用他莫昔芬的乳腺癌患者中进行的前瞻性、自身对照、药代动力学研究。依度沙班的剂量为 60mg，每日一次，连续 4 天，首先无他莫昔芬，然后在稳态时同时使用他莫昔芬。在依度沙班的两个序列的第 4 天，采集了一系列血样。使用非线性混合效应模型建立了群体药代动力学模型，以评估他莫昔芬对依度沙班清除率的影响。此外，还估计了平均曲线下面积（AUC）。如果几何均数（GLM）比值的 90%置信区间（CI）在 80%-125%的无效应范围内，则认为无相互作用。

结果

共纳入 24 名计划使用他莫昔芬的乳腺癌患者。中位年龄为 56 岁（IQR，51-63）。依度沙班的平均清除率为 32.0L/h（95%CI，11.1-35.0L/h）。与无他莫昔芬时相比，他莫昔芬对依度沙班清除率无影响，清除率为 100%（95%CI，92%-108%）。无他莫昔芬时 AUC 的平均值为 1923ngh/ml（SD，695），有他莫昔芬时 AUC 的平均值为 1947ngh/ml（SD，595）（GLM-比值 100.4；90%CI，98.6-102.2）。