Application of a microdosed cocktail of 3 oral factor Xa inhibitors to study drug–drug interactions with different perpetrator drugs. Issue 8 (27th March 2020)

• Record Type: Journal Article
• Authors: Mikus, Gerd; Foerster, Kathrin I.; Schaumaeker, Marlene; Lehmann, Marie‐Louise; Burhenne, Jürgen; Haefeli, Walter E.
• Is Part Of: British journal of clinical pharmacology. Volume 86:Issue 8(2020)
• Page Start: 1632
• Page End: 1641
• Publication Date: 2020-03-27
• Subjects: apixaban -- cobicistat -- drug interaction -- edoxaban -- rifampicin -- rivaroxaban -- voriconazole; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14277
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : 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).