期刊
DRUG METABOLISM AND PHARMACOKINETICS
卷 35, 期 1, 页码 151-159出版社
JAPANESE SOC STUDY XENOBIOTICS
DOI: 10.1016/j.dmpk.2019.10.005
关键词
Apixaban; Rivaroxaban; Edoxaban; Atrial fibrillation; Venous thromboembolism; anti-FXa activity; Plasma concentration; Population pharmacokinetics
Background: The anticoagulant actions of oral direct factor Xa (FXa) inhibitors can be inferred from their observed plasma concentrations; however, the steady-state pharmacokinetics (PK) of different FXa inhibitors have not been compared in clinically. Methods: The sensitivity of the rivaroxaban, apixaban, and edoxaban in the STA-Liquid Anti-FXa assay were compared, and the anti-FXa plasma concentrations were measured for PK assessments. Nonlinear mixed-effects modeling was used to assess population PK in 329 patients with nonvalvular atrial fibrillation or venous thromboembolism. Patients were followed up for an average of 3.6 years. Results: Sensitivity was similar among the three drugs in this assay, which could directly compare plasma concentrations instead of anti-FXa activities. Overall exposure was greatest in 5 mg BID apixaban relative to other drugs (p < 0.001). The geometric mean AUC for the 0 to 24-h interval was 4550 ng h/mL for apixaban, 2710 ng h/mL for 15 mg QD rivaroxaban, and 1290 ng h/mL for 60 mg QD edoxaban. The PKs of 2.5 mg BID apixaban or 15 mg QD rivaroxaban were associated with hemorrhagic events. Conclusions: Apixaban was associated with greater exposure, higher trough concentrations in plasma compared with rivaroxaban or edoxaban. Furthermore, a higher plasma concentration may partially predict hemorrhagic events. (C) 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd.
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