Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Clin Pharmacokinet. 2022 Jan;61(1):97-109. doi: 10.1007/s40262-021-01051-9. Epub 2021 Jul 17.
Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly.
In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals.
Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration-time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold).
Drug-drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible.
EudraCT number: 2017-004453-16.
越来越多地使用 Xa 因子抑制剂（FXaIs），但缺乏充分的药物相互作用数据。采用微量鸡尾酒方法可以支持快速填补知识空白。
在一项随机交叉试验中，我们研究了六种口服唑类抗真菌药与包含 25 µg 利伐沙班、25 µg 阿哌沙班和 50 µg 依度沙班的微量 FXaI 鸡尾酒之间的药物相互作用。此外，还采用微量鸡尾酒方法监测不同的酶活性。六种不同的唑类抗真菌药以治疗剂量给药 24 小时，而微量鸡尾酒在唑类抗真菌药给药 1 小时后给药。
酮康唑和泊沙康唑是最强的诱导剂，与阿哌沙班（AUC 比值 [AUCR] 分别为 1.64 和 1.62）和依度沙班（AUCR 分别为 2.08 和 2.1）相似，而酮康唑使利伐沙班增加 2.32 倍，但仅使泊沙康唑增加 1.37 倍。所有其他唑类抗真菌药对 FXaIs 的诱导作用较小。酮康唑也被证实是最强的 CYP3A 抑制剂（8.42 倍），使用微量咪达唑仑证实了 CYP3A 抑制作用。
使用微量鸡尾酒方法可以研究同一药物类别（FXaIs）中三种药物的药物相互作用，这些药物具有不同的清除机制。使用唑类抗真菌药物作为诱导剂，可以在一项试验中研究多种相互作用，并对潜在的相互作用机制有更详细的了解。
EudraCT 编号：2017-004453-16。
