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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers
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Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers

机译：健康志愿者中药物相互作用中酮康唑相关的肝损伤

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摘要

Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.
机译：酮康唑是体内有效的CYP3A抑制剂，在与健康志愿者进行的药物-药物相互作用（DDI）研究中经常用作索引CYP3A抑制剂。美国，欧盟和其他地方的监管机构最近对此类研究限制了全身使用酮康唑的使用。在DDI研究中，酮康唑相关的肝损伤风险被认为是这些措施的主要依据。为了评估这些限制的基础，我们分析了一系列已发表的DDI研究，这些研究是从对现有文献的回顾中确定的。该研究集由53项DDI研究组成，除受害药物外，还包括971名全身性酮康唑暴露的健康志愿者。在4名受试者中观察到了与酮康唑相关的指示肝损伤的血清化学值异常，在研究人群中患病率为0.41％。没有重大不良反应或肝功能衰竭。终止酮康唑治疗后，所有表明肝损伤的异常均得到解决。该评价的发现不支持在涉及健康志愿者的DDI研究中限制酮康唑作为CYP3A指数抑制剂。

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