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

Abstract

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.

Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk

“…Because we assessed patients who were actively hospitalized, bleeding risk may have been increased due to factors that could not be fully assessed retrospectively (e.g., endothelial injury). However, the rates of bleeding observed in our study were consistent with what was expected based on prior literature 13–17 . Additionally, the duration of concomitant administration of fluconazole with DOAC was short at 4 days (IQR 3–7), which may have impacted the number of bleeding events based on the expected drug–drug interaction.…”

“…The study conducted in Taiwan found an increased risk of major bleeding in patients with nonvalvular atrial fibrillation with concomitant fluconazole and DOAC use (adjusted incidence rate 2.35 overall, 2.26 with dabigatran, 2.25 with rivaroxaban, and 3.36 with apixaban) 7 . The study unexpectedly found no increased bleeding risk with other azole antifungals that are more potent CYP3A4 inhibitors (voriconazole and posaconazole) compared with fluconazole 7,9,17 . This study was limited to patients with nonvalvular atrial fibrillation, whereas our study included both patients with atrial fibrillation and VTE.…”

“…When assessing pharmacokinetic data, one study of rivaroxaban co‐administered with fluconazole in healthy volunteers demonstrated an increase in the rivaroxaban area under the curve (AUC) 6 . Conversely, another study found no significant increase in AUC or maximum serum concentration (Cmax) of apixaban after a single co‐administration with fluconazole in healthy volunteers but did find an increase in AUC and Cmax with posaconazole, voriconazole, itraconazole, and isavuconazole 17 . A post hoc analysis of patients with atrial fibrillation in the ARISTOTLE trial found that 21% of patients receiving apixaban were also taking a medication that inhibited CYP3A4 and/or P‐gp, but no difference in the rate of major bleeding was observed in these patients 18 …”

Pharmacokinetics of a microdosed cocktail of three direct oral anticoagulants in children with congenital heart defects: study protocol for a single-centre clinical trial (DOAC-Child)

“…An oral microdose DOAC cocktail (µ-FXaI) containing apixaban (25 µg), edoxaban (50 µg) and rivaroxaban (25 µg) has been successfully used in adults to study drug–drug interactions 5 6. Comparing the PK of these 3 µ-FXaI, obtained after simultaneous administration, with the PK after therapeutic DOAC doses from the literature showed DOAC clearances always in the same range (dose-proportional PK) 7–9.…”

Evaluation of bleeding and anticoagulation markers by edoxaban and low‐dose cyclosporine: A case series study

“…The edoxaban plasma concentration increases with the co‐administration of verapamil, amiodarone, and azole antifungals (Mendell et al., 2013; Mikus et al., 2020; Rohr et al., 2022). Moreover, a drug–drug interaction study demonstrated that cyclosporine at a single oral dose of 500 mg dramatically elevated not only the maximum plasma concentration of edoxaban (245.7 ng/mL vs. 410.9 ng/mL) via the inhibition of P‐glycoprotein but also that of the active metabolite of edoxaban (M4) (23.2 ng/mL vs. 191.1 ng/mL) via the inhibition of organic anion transporter 1B1 (OATP1B1) (Parasrampuria et al., 2016).…”