Tibotec BVBA, Mechelen, Belgium.
Clin Ther. 2010 Feb;32(2):328-37. doi: 10.1016/j.clinthera.2010.02.013.
Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against both wild-type HIV and viruses harboring NNRTI resistance. Etravirine is mainly eliminated via the hepatobiliary route.
This study in HIV- patients with mild or moderate hepatic impairment and healthy matched controls was conducted to explore the effects of mild and moderate hepatic impairment on the steady-state pharmacokinetics of etravirine and to provide guidance for the treatment of HIV+ patients with hepatic impairment.
This open-label, multiple-dose study enrolled HIV- patients aged 18 to 65 years with mild or moderate hepatic impairment (Child-Pugh score, 5-6 or 7-9, respectively) and healthy volunteers matched for age, sex, race, and body mass index (BMI). All subjects received etravirine 200 mg BID with food for 7 days and a morning dose on day 8. Etravirine pharmacokinetics over a period of 12 hours on days 1 and 8 were determined using noncompartmental methods and analyzed using linear mixed-effects modeling. Tolerability of etravirine was assessed based on the reported adverse events, laboratory investigations, ECG, and physical examination.
Each group comprised 8 subjects (mild hepatic impairment patients: 5 men, 3 women; median age, 57 years [range, 41-65 years]; BMI, 26 kg/m(2) [range, 20-32 kg/m(2)]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44-64 years]; BMI, 26 kg/m(2) [range, 22-32 kg/m(2)]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the log transformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: C(min), 0.87 (0.65-1.17) and 0.98 (0.68-1.42) microg/mL; C(max), 0.79 (0.63-1.00) and 0.72 (0.54-0.96) ug/mL; and AUC(0-12), 0.87 (0.69-1.09) and 0.82 (0.60-1.11) microg/mL/h. All treatment-emergent adverse events were considered mild to moderate; the most common were headache (50% in healthy controls) and fatigue and nausea (both 25% in patients with mild hepatic impairment). No clinically significant changes in laboratory parameters, physical examination including vital signs, or ECG were observed. One serious adverse event was reported during the follow-up period in a patient with moderate hepatic impairment due to hepatic cirrhosis secondary to alcoholism. This patient presented at screening with dilated cardiomyopathy and cardiac arrhythmia.
In this Phase I pharmacokinetic study, no clinically relevant differences were observed between patients with mild or moderate hepatic impairment and healthy matched subjects with regard to the pharmacokinetics of etravirine. Based on these findings in these HIV- volunteers, no dose adjustment of etravirine appears to be necessary in patients with mild or moderate hepatic impairment. Etravirine was generally well tolerated.
依曲韦林是一种非核苷类逆转录酶抑制剂（NNRTI），对野生型 HIV 和携带 NNRTI 耐药性的病毒均具有活性。依曲韦林主要通过肝胆途径消除。
本研究在 HIV- 合并轻度或中度肝损伤的患者和健康匹配对照者中进行，旨在探讨轻度和中度肝损伤对依曲韦林稳态药代动力学的影响，为治疗肝损伤的 HIV+ 患者提供指导。
这项开放标签、多剂量研究纳入了年龄在 18 至 65 岁之间、合并轻度或中度肝损伤（Child-Pugh 评分分别为 5-6 或 7-9）的 HIV- 患者和年龄、性别、种族和体重指数（BMI）相匹配的健康志愿者。所有受试者均接受依曲韦林 200mg 每日两次（BID）随餐给药，第 8 天加用一次晨服剂量。采用非房室模型法测定第 1 天和第 8 天的 12 小时依曲韦林药代动力学，并采用线性混合效应模型进行分析。根据不良事件、实验室检查、心电图和体格检查报告来评估依曲韦林的耐受性。
每组均包括 8 例患者（轻度肝损伤患者：5 例男性，3 例女性；中位年龄为 57 岁[范围，41-65 岁]；BMI 为 26kg/m2[范围，20-32kg/m2]；中度肝损伤患者：6 例男性，2 例女性；年龄为 54 岁[范围，44-64 岁]；BMI 为 26kg/m2[范围，22-32kg/m2]）。所有患者均为白种人，且为轻度吸烟者。第 8 天，轻度和中度肝损伤患者的依曲韦林药代动力学参数的最小二乘均值比值（90%CI）分别为：Cmin，0.87（0.65-1.17）和 0.98（0.68-1.42）μg/mL；Cmax，0.79（0.63-1.00）和 0.72（0.54-0.96）μg/mL；AUC0-12，0.87（0.69-1.09）和 0.82（0.60-1.11）μg/mL/h。所有治疗出现的不良事件均为轻度至中度；最常见的不良事件为头痛（健康对照组为 50%）和疲劳及恶心（轻度肝损伤患者均为 25%）。未观察到实验室参数、包括生命体征在内的体格检查或心电图有临床意义的变化。一名中度肝损伤患者在随访期间报告了 1 例严重不良事件，该患者因酒精性肝硬化导致肝损伤，且在筛查时即存在扩张型心肌病和心律失常。
在这项 I 期药代动力学研究中，与健康匹配对照者相比，轻度或中度肝损伤患者的依曲韦林药代动力学未见临床相关差异。基于这些 HIV- 志愿者中的发现，轻度或中度肝损伤患者似乎无需调整依曲韦林的剂量。依曲韦林总体耐受性良好。
