Anne-Laure Sennesael1, Anne-Sophie Larock2, Philippe Hainaut3, Sarah Lessire4, Michael Hardy5, Jonathan Douxfils6, Anne Spinewine7, François Mullier8. 1. Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Yvoir, Belgium; Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. Electronic address: anne-laure.sennesael@uclouvain.be. 2. Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Yvoir, Belgium. 3. Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Department of Internal Medicine, Brussels, Belgium. 4. Université catholique de Louvain, CHU UCL Namur, NTHC, NARILIS, Department of Anesthesiology, Yvoir, Belgium. 5. Université catholique de Louvain, CHU UCL Namur, NTHC, NARILIS, Department of Anesthesiology, Yvoir, Belgium; Université catholique de Louvain, CHU UCL Namur, NTHC, NARILIS, Hematology Laboratory, Yvoir, Belgium. 6. Department of Pharmacy, NTHC, NARILIS, Université de Namur, Namur, Belgium; Qualiblood sa, Namur, Belgium. 7. Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Yvoir, Belgium; Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. 8. Université catholique de Louvain, CHU UCL Namur, NTHC, NARILIS, Hematology Laboratory, Yvoir, Belgium.
Abstract
PURPOSE: The concomitant use of direct oral anticoagulants (DOAC) and strong P-gp and CYP3A4 inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. METHODS: We retrospectively identified hospitalized patients receiving simultaneously a DOAC and carbamazepine, phenobarbital, phenytoin or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady-state were included. DOAC peak or trough levels were compared to on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. RESULTS: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). CONCLUSION: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.
PURPOSE: The concomitant use of direct oral anticoagulants (DOAC) and strong P-gp and CYP3A4 inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. METHODS: We retrospectively identified hospitalized patients receiving simultaneously a DOAC and carbamazepine, phenobarbital, phenytoin or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady-state were included. DOAC peak or trough levels were compared to on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. RESULTS: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). CONCLUSION: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.
Authors: Matteo Candeloro; John W Eikelboom; Noel Chan; Vinai Bhagirath; James D Douketis; Sam Schulman Journal: Res Pract Thromb Haemost Date: 2022-02-17