Application of a microdosed cocktail of 3 oral factor Xa inhibitors to study drug-drug interactions with different perpetrator drugs.

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).

Microdosed Cocktail of Three Oral Factor Xa Inhibitors to Evaluate Drug-Drug Interactions with Potential Perpetrator Drugs.

OBJECTIVES: The aim of this study was to prove the suitability of simultaneously administered microdoses of the factor Xa inhibitors (FXaIs) rivaroxaban, apixaban and edoxaban (100 µg in total). To evaluate drug-drug interactions, the impact of ketoconazole, a known strong inhibitor of cytochrome P450 3A4 and P-glycoprotein, was studied. METHODS: In a crossover clinical trial, 18 healthy volunteers were randomized to the two treatments using microdoses of rivaroxaban, apixaban and edoxaban alone and when coadministered with ketoconazole. Plasma and urine concentrations of microdosed apixaban, edoxaban and rivaroxaban were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification of 2.5 pg/ml. RESULTS: The microdosed FXaI cocktail showed similar pharmacokinetic parameters compared with published data, using normal therapeutic doses of each FXaI. Ketoconazole significantly increased exposure, with geometric mean AUC ratios of 1.90 (apixaban), 2.35 (edoxaban) and 2.27 (rivaroxaban). CONCLUSION: The microdosed FXaI cocktail approach was able to precisely predict the drug interaction with ketoconazole. This is the first study that has been conducted to evaluate drug-drug interactions with a drug class, and the low administered doses also allow evaluation in vulnerable target populations. STUDY PROTOCOL: EudraCT 2016-003024-23.