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.

Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 μg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 in the presence and absence of a strong inhibitor (voriconazole). Without voriconazole, omeprazole exposure was dose-proportional irrespective of the genotype, but in PMs geometric mean ratios (GMRs) of AUC 0-∞ were 6.6-fold higher and molar metabolic ratios of 5-OH omeprazole/omeprazole approximately 10-fold lower. Voriconazole increased omeprazole exposure in EMs approximately 5-fold (AUC 0-4 GMR after 100 μg omeprazole, 4.61; 90% confidence interval [CI], 2.69-7.89; AUC 0-4 GMR after 20 mg omeprazole, 5.5; 90%CI, 1.07-1.46), whereas no clinically significant impact on PK in PMs was observed (GMR AUC 0-4 after 100 μg omeprazole, 1.29; 90%CI, 0.81-2.04; GMR AUC 0-4 after 20 mg omeprazole, 1.25; 90%CI, 1.07-1.46). Linear regression and Bland-Altman analyses revealed excellent agreement between AUC 0-∞ and AUC 0-4 of omeprazole (r 2 = 0.987; bias, 0.35%; 95%CI, −3.197% to 3.89%) and also the molar metabolic ratio, 5-OH omeprazole/omeprazole (r 2 = 0.987; bias, −3.939; 95%CI, −9.06% to −1.18%), suggesting that an abbreviated sampling protocol can be used for intravenous CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of intravenous omeprazole microdoses closely reflects the changes observed with regular omeprazole doses; however, to avoid autoinhibition of probe drugs, microdosing appears to be the favorable technique.

A critically ill patient with multiple postoperative infections repeatedly required profound voriconazole dose reductions whenever high-dose meropenem was added. Subsequent in vitro assessment confirmed inhibition of cytochrome P450 (CYP) 2C19 and CYP3A4 by meropenem, suggesting that during meropenem treatment, narrow therapeutic index drugs metabolized by these CYPs require close monitoring.