Key result
Ketoconazole and posaconazole were the strongest perpetrators of drug-drug interactions, with ketoconazole increasing the area under the curve of rivaroxaban by 2.32-fold, edoxaban by 2.08-fold, and apixaban by 1.64-fold.
Why the study?
Factor Xa inhibitors are increasingly used despite lacking sufficient drug-drug interaction data.
Do oral azole antifungals alter the pharmacokinetics of microdosed factor Xa inhibitors in healthy volunteers?
RCT (n=12)
Open-label
Randomized crossover
No
Do oral azole antifungals alter the pharmacokinetics of microdosed factor Xa inhibitors in healthy volunteers?
Effect estimate: AUCR 2.32
p-value: p=<0.05
Ketoconazole and posaconazole significantly increase the exposure of factor Xa inhibitors, highlighting the need for potential dose adjustments during coadministration.
Requires caution with ketoconazole or posaconazole in DOAC users; extends DDI evidence but leaves outcome data open.
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.
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Rohr et al. (2021) conducted an RCT in Healthy volunteers (n=12). Azole antifungal drugs (ketoconazole, posaconazole, itraconazole, voriconazole, fluconazole, isavuconazole) vs. Baseline (FXaI cocktail alone) was evaluated on Area under the concentration-time curve ratio (AUCR) of FXaIs (AUCR 2.32, p=<0.05). Ketoconazole and posaconazole were the strongest perpetrators of drug-drug interactions, with ketoconazole increasing the area under the curve of rivaroxaban by 2.32-fold, edoxaban by 2.08-fold, and apixaban by 1.64-fold.
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