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Aims Using 3 different perpetrators the impact of voriconazole, cobicistat and rifampicin (single dose), we evaluated the suitability of a microdose cocktail of factor Xa inhibitors (FXaI; rivaroxaban, apixaban and edoxaban; 100 μg in total) to study drug–drug interactions. Methods Three cohorts of 6 healthy volunteers received 2 treatments with microdoses of rivaroxaban, apixaban and edoxaban alone and with coadministration of 1 of the perpetrators. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra‐performance liquid chromatography–tandem mass spectrometry with a lower limit of quantification of 2.5 pg/mL. Results Voriconazole caused only a minor interaction with apixaban and rivaroxaban, none with edoxaban. Cobicistat significantly increased exposure of all 3 FXaI with area under the plasma concentration–time curve ratios of 1.67 (apixaban), 1.74 (edoxaban) and 2.0 (rivaroxaban). A single dose of rifampicin decreased the volume of distribution and elimination half‐life of all 3 FXaI. Conclusions The microdosed FXaI cocktail approach is able to generate drug interaction data and can help elucidating the mechanism involved in the clearance of the different victim drugs. This is a safe approach to concurrently study drug–drug interactions with a drug class. (EudraCT 2016–003024‐23).

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