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).
Keywords: apixaban; cobicistat; drug interaction; edoxaban; rifampicin; rivaroxaban; voriconazole.
© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.