Department of Pharmacy, Centre Hospitalier Universitaire (CHU) UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Université catholique de Louvain, Yvoir, Belgium; Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Department of Pharmacy, Centre Hospitalier Universitaire (CHU) UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Université catholique de Louvain, Yvoir, Belgium.
Am J Med. 2021 Oct;134(10):1295-1299. doi: 10.1016/j.amjmed.2021.06.003. Epub 2021 Jun 25.
The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (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.
We retrospectively identified hospitalized patients simultaneously receiving 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 with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified.
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).
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.
直接口服抗凝剂（DOAC）与强 P-糖蛋白（P-gp）和细胞色素 P450 3A4（CYP3A4）诱导剂同时使用可能导致 DOAC 水平降低和治疗失败。本研究旨在描述同时接受强 P-gp 和 CYP3A4 诱导剂治疗的患者的 DOAC 浓度，以及与 DOAC 水平高低相关的个体危险因素。
我们回顾性地确定了 2016 年至 2021 年间同时接受 DOAC 和卡马西平、苯巴比妥、苯妥英或利福平治疗的住院患者。其中，纳入了在稳态下进行 DOAC 测量的患者。比较 DOAC 峰或谷水平与关键试验中观察到的治疗范围。确定了 DOAC 水平高低的个体危险因素。
我们纳入了 17 名患者（中位年龄 75 岁），主要接受阿哌沙班和卡马西平治疗。对于 5 名患者（29%），DOAC 谷或峰水平低于预期范围。在其余 12 名患者中，8 名患者至少有一次测量值处于范围的较低四分位。药物蓄积风险因素中位数为 0（范围 0-1）的患者有至少一次测量值低于范围，而其他患者为 2（范围 0-3）。9 名患者（增加 DOAC 剂量或更换药物）根据 DOAC 测量结果进行了治疗调整。
我们的数据表明，接受强 P-gp 和 CYP3A4 诱导剂治疗的患者 DOAC 水平降低的风险显著增加，尤其是无药物蓄积危险因素的患者。DOAC 测量有助于管理这种相关的药物相互作用。
