Population Pharmacokinetics of Edoxaban in Chinese Patients With Non-Valvular Atrial Fibrillation

This is an open label study. Male or female patients with non-valvular atrial fibrillation (NVAF) with age ≥20 years, and meeting the indications of edoxaban are potentially eligible for the study. Patients receive Edoxaban 15mg、30mg or 60mg according to the criteria as following:

• Patients with severe renal insufficiency (15ml/min ≤ CrCl <30ml/min), 15mg quaque die (QD)
• Patients with normal or mild renal insufficiency (CrCl ≥50ml/min), 60mg QD
• Patients with moderate renal insufficiency (30ml/min ≤ CrCl <50ml/min), weight ≤60kg or combined use of P-gp inhibitors (such as dronedarone，ketoconazole, erythromycin, etc), 30mg QD.

Patients will receive clinical evaluation at screening period, 4 weeks、8 weeks and 12 weeks after administration with Edoxaban. The following clinical evaluation items were included: body weight, vital signs (blood pressure and heart rate), CHADS2-VAS score, concomitant medication, ECG and echocardiogram, laboratory examination, safety evaluation (thromboembolic events, bleeding events, death) during treatment.

Additional blood samples are collected for pharmacokinetic evaluation at screening period, pre-dose, 2±1h and 6±1h after administration at 4-, 8-, and 12-week visit, and for pharmacodynamic evaluation (FXa) at screening period, pre-dose after administration at 4-, 8-, 12-week visit.

The population pharmacokinetics of Edoxaban in Chinese patients with non-valvular atrial fibrillation will be determined after 12weeks clinical observation.

The ENGAGE PopPK model suitable in Chinese Patients with Non-Valvular Atrial Fibrillation will be established.

Safety outcomes (thromboembolic events, bleeding events, death) will be evaluated.

Inclusion criteria

• Male or female NVAF patients, who need anticoagulant therapy at least 3 months
• Age ≥20 years,
• Creatinine clearance rate ≥ 15 ml/min
• Sign a written informed consent form (ICF) for participating in the study
• No simultaneous participation in any interventional study

Exclusion criteria

• Patients with the Valve replacement
• Patients with valvular atrial fibrillation
• Mild and severe anemia patients
• CrCl<15ml/min
• Patients on dialysis, risk of bleeding, taking antiplatelet drugs, or taking other anticoagulants
• Contraindicated to Edoxaban.
• Life expectancy < 6 months.
• Hypertension defined as systolic and/or diastolic blood pressure > 95th age percentile or poorly controlled hypertension
• Hepatic disease which is associated either: with coagulopathy leading to a clinically relevant bleeding risk, or alanine transaminase (ALT) > 5x upper level of normal (ULN), or total bilirubin > 2x ULN with direct bilirubin > 20% of the total.
• Active bleeding or high risk for bleeding contraindicating anticoagulant therapy. For example：

• a history of intracranial, intraocular, intraspinal, retroperitoneal, or traumatic intra-articular bleeding
• gastrointestinal bleeding during the prior year
• peptic ulcer within the previous 90 days
• surgery or injury requiring hospitalization within the previous 30 days
• hemoglobin <9 g/dl or a platelet count <50×109/L
• active bleeding at registration
• any procedure associated with bleeding planned to occur during the treatment period
• Urine pregnancy test positive if female
• Inability to cooperate with the study procedures
• Participation in a study with an investigational drug or medical device within 30 days prior to screening
• Additional exclusion criteria included, but were not limited to:

• cerebral infarction or transient ischemic attack within the past 30 days
• comorbid rheumatic valvular disease
• comorbid infective endocarditis or atrial myxoma
• evidence of thrombus in the left ventricle or atrium, or hereditary tendency for thrombus formation scheduled electrical or pharmacological defibrillation during the treatment period
• acute myocardial infarction, or unstable angina
• a diagnosis of active malignant tumor or cancer treatment within the past 5 years
• previous treatment with Edoxaban