Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Clin Pharmacokinet. 2019 Sep;58(9):1155-1163. doi: 10.1007/s40262-019-00749-1.
The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug-drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied.
In a crossover clinical trial, 18 healthy volunteers were randomized to the two treatments using microdoses of rivaroxaban, apixaban and edoxaban alone and when coadministered with ketoconazole. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification of 2.5 pg/ml.
The microdosed FXaI cocktail showed similar pharmacokinetic parameters compared with published data, using normal therapeutic doses of each FXaI. Ketoconazole significantly increased exposure, with geometric mean AUC ratios of 1.90 (apixaban), 2.35 (edoxaban) and 2.27 (rivaroxaban).
The microdosed FXaI cocktail approach was able to precisely predict the drug interaction with ketoconazole. This is the first study that has been conducted to evaluate drug-drug interactions with a drug class, and the low administered doses also allow evaluation in vulnerable target populations.
EudraCT 2016-003024-23.
本研究旨在证明同时给予小剂量的因子 Xa 抑制剂（FXaIs）利伐沙班、阿哌沙班和依度沙班（共 100μg）的适用性。为了评估药物相互作用，研究了酮康唑（一种已知的细胞色素 P450 3A4 和 P-糖蛋白的强抑制剂）的影响。
在一项交叉临床试验中，18 名健康志愿者被随机分为单独使用小剂量利伐沙班、阿哌沙班和依度沙班以及与酮康唑联合使用这两种治疗方法的两组。使用经过验证的超高效液相色谱-串联质谱法，以 2.5pg/ml 的定量下限定量测定微剂量阿哌沙班、依度沙班和利伐沙班的血浆和尿液浓度。
与每种 FXaI 的正常治疗剂量相比，微剂量 FXaI 鸡尾酒显示出相似的药代动力学参数。酮康唑显著增加了暴露量，阿哌沙班、依度沙班和利伐沙班的几何均数 AUC 比值分别为 1.90、2.35 和 2.27。
微剂量 FXaI 鸡尾酒方法能够准确预测与酮康唑的药物相互作用。这是首次进行的评估药物相互作用的药物类别研究，并且给予的低剂量也允许在脆弱的目标人群中进行评估。
EudraCT 2016-003024-23。
