Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, 46285, USA,
Eur J Clin Pharmacol. 2013 Dec;69(12):2011-9. doi: 10.1007/s00228-013-1572-y. Epub 2013 Aug 17.
To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine.
Two separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child-Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft-Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration-time data.
In the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h × ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of Cmax was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events.
PK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.
评估肝或肾功能损害对依度沙班（edivoxetine）药代动力学（PK）的影响。
进行了两项分别针对男性和女性的多中心、开放性研究，根据肝功能（Child-Pugh 分类）或肾功能（Cockcroft-Gault 方程计算的肌酐清除率）对受试者进行分类。受试者在肝损伤研究中接受 18mg 单剂量或在肾损伤研究中接受 6mg 单剂量。从依度沙班血浆浓度-时间数据计算非房室 PK 参数。
在肝损伤研究中，轻度、中度和重度组的 [损害：正常]比值的几何均数最小二乘均值（GLSM）和 90%置信区间（CI）分别为 1.24（0.93，1.64）、1.60（1.21，2.12）和 1.70（1.28，2.24）。在肾损伤研究中，轻度、中度、重度和终末期肾病（ESRD）组的 [损害：正常]比值 AUC0-∞的 GLSM（90%CI）分别为 1.13（0.73，1.73）、1.90（1.28，2.82）、1.55（0.94，2.55）和 1.03（0.66，1.59）。总体而言，肝和肾损伤组的 [损害：正常]比值 Cmax 的 GLSM 略小于或接近 1。在两项研究中，生命体征和实验室值均无临床显著变化，不良事件的严重程度为轻度，主要与神经系统和胃肠道紊乱相关事件有关。
肝或肾损伤受试者的 PK 变化幅度较小，似乎不会影响总体受试者的耐受性。在更大的损伤人群中，包括同时存在双重损伤的人群中，每日给予依度沙班治疗，将有助于在临床实践中确定依度沙班的耐受性和 PK。
