A mechanism-based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID-19 treatment in humans.
A mechanism-based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID-19 treatment in humans.
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DOI：
10.1002/psp4.12584
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Rao GG
中科院分区：
文献类型：
--
作者：
Hanafin PO;Jermain B;Hickey AJ;Kabanov AV;Kashuba AD;Sheahan TP;Rao GG
截至 2020 年 10 月 26 日，严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的爆发引发了全球 2019 年冠状病毒病 (COVID-19) 大流行，导致全球确诊感染人数达到 4290 万人，死亡人数超过 110 万人。瑞德西韦是一种广谱核苷酸前药，可有效对抗地方性冠状病毒。最近描述了瑞德西韦在血浆中的药代动力学（PK）。然而，其活性代谢物三磷酸核苷（NTP）在人类肺部感染部位的分布尚不清楚。我们的目标是利用瑞德西韦及其代谢物现有的小鼠体内 PK 数据开发一种基于机制的模型，以异速缩放和模拟血浆中瑞德西韦和肺匀浆中 NTP 的人体 PK。皮下注射 25 或 50 mg/kg 瑞德西韦的 Ces1c −/− 小鼠的血浆中瑞德西韦和 GS-441524 浓度以及肺匀浆中的总磷酸化核苷浓度同时适合估计 PK 参数。对小鼠 PK 模型进行异速缩放以预测人类 PK 参数，以模拟临床推荐的 200 mg 负荷剂量，然后以 30 分钟静脉输注的形式每日 100 mg 维持剂量。模拟人血浆中未结合的瑞德西韦浓度低于 2.48 μM，即体外抑制 SARS-CoV-2 的 90% 最大抑制浓度。肺部 NTP 模拟低于体外高效阈值。我们已经确定需要替代剂量策略，以在人肺中实现更有效的 NTP 浓度，或许可以通过重新配制瑞德西韦以进行直接肺部递送。
The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) outbreak initiated the global coronavirus disease 2019 (COVID‐19) pandemic resulting in 42.9 million confirmed infections and > 1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad‐spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PKs) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism‐based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS‐441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c −/− mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30‐minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 μM, the 90% maximal inhibitory concentration for SARS‐CoV‐2 inhibition in vitro. Simulations of NTP in the lungs were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lungs, perhaps by reformulating remdesivir for direct pulmonary delivery.
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