Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.
Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.
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DOI：
10.1111/cts.12421
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Shapiro D
中科院分区：
文献类型：
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作者：
Edwards JE;LaCerte C;Peyret T;Gosselin NH;Marier JF;Hofmann AF;Shapiro D
奥贝胆酸（OCA）是一种半合成胆汁酸，是一种选择性和有效的法尼醇X受体（FXR）激动剂，用于治疗慢性非病毒性肝病。生理药代动力学模型先前已用于描述胆汁酸的吸收、分布、代谢和排泄（ADME）。在健康志愿者和糖尿病受试者中测量OCA血浆水平。建立了一个生理药代动力学模型，以定量描述OCA在有和无肝损害患者中的ADME。轻度、中度和重度肝损害受试者中预测和观察到的全身OCA暴露量增加之间具有良好的一致性，分别为健康志愿者的1.4、8和13倍。轻度、中度和重度肝损害受试者的预测肝脏暴露量仅增加1.1、1.5和1.7倍。在肝硬化受试者中，肝脏（药理学活性的主要部位沿着肠道）中的OCA暴露量略有增加（约2倍）。
Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4‐, 8‐, and 13‐fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1‐, 1.5‐, and 1.7‐fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2‐fold).