Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral Factor Xa Inhibitors Administered as a Microdosed Cocktail

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: EudraCT number: 2017-004453-16. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01051-9.