Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs?An in vitro and in vivo DMPK assessment

• 作者: Jiashu Xie Zhengqiang Wang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Original articles
• 页码范围: 1607-1616
• 页数: 10页
• 语种: 英文

摘要

Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical out-comes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and phar-macokinetics (DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes (HLMs,t1/2 =～ 1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphor-amidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57％.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.