No clinically relevant interaction of voriconazole with microdosed apixaban, edoxaban and rivaroxaban

[Speaker] Gerd Mikus:1
[Co-author] Marlene Schaumaeker:1, Kathrin Foerster:1, Marie-Louise Lehmann:1, Walter E Haefeli:1
1:Clinical Pharmacology and Pharmacoepidemiology, Universtity of Heidelberg, Germany

The direct oral anticoagulants (DOAC) apixaban, edoxaban, and rivaroxaban are factor Xa inhibitors and plasma concentrations predict the pharmacological effect. In order to facilitate more knowledge for the decision which one to use in individual patients with their co-medication, we explored the use of a microdosed cocktail of the 3 DOACs. In comparison to ketoconazole the effect of voriconazole as an inhibitor of multiple CYP enzymes was studied in healthy volunteers. This randomised study was approved by the German competent authority and the local ethics committee. Six participants took the DOAK cocktail alone or in combination with ketoconazole (400mg qd, starting 1 day before the DOAC administration) or in combination with voriconazole (400mg bid, starting 1 day before the DOAC administration, 200mg bid thereafter). Microdosed midazolam was used on every occasion to monitor CYP3A activity. Solutions of the DOACs were prepared by the hospital pharmacy. Final drinking solution of apixaban (25ug), edoxaban (50ug), and rivaroxaban (25ug) were prepared just before intake. A 24 h pharmacokinetic profile was obtained. Plasma concentrations of microdosed apixaban, edoxaban, and rivaroxaban were quantified using an according to FDA & EMA guidelines validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay with a LLOQ of 2.5 pg/ml. Simultaneous administration of the DOAK cocktail shows similar pharmacokinetic data compared to published data using a normal therapeutic dose. Voriconazole increased exposure of all 3 DOAKs with an AUCR of 1.33 (apixaban), 1.26 (edoxaban), and 1.31 (rivaroxaban). In contrast, the effect of ketoconazole was much more pronounced with an AUCR of 2.08 (apixaban), 2.71 (edoxaban), and 2.30 (rivaroxaban). CYP3A activity was efficiently decreased by voriconazole and ketoconazole with an AUCR of 8.18 and 8.41, respectively. Using this microdosing approach no dose adjustment is recommended for each DOAC when voriconazole treatment is initiated.
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