Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2
Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2
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DOI：
10.1128/aac.02428-20
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发表时间：
2021-05-01
影响因子：
4.9
通讯作者：
Painter, George R.
中科院分区：
文献类型：
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作者：
Painter, Wendy P.;Holman, Wayne;Painter, George R.
Molnupiravir (EIDD-2801/MK-4482) 是活性抗病毒核糖核苷类似物 β-D-N4-羟基胞苷 (NHC; EIDD-1931) 的前药，具有对抗多种 RNA 病毒的活性，包括严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)、严重急性呼吸综合征冠状病毒 (SARS-CoV)、中东呼吸综合征冠状病毒 (MERS-CoV) 以及季节性和大流行性病毒流感病毒。在这项首次非人类、1 期、随机、双盲、安慰剂对照研究中，对健康志愿者进行了单剂量和多剂量莫努匹拉韦的评估，其中包括评估食物对药代动力学的影响。 EIDD-1931 在血浆中迅速出现，观察到的最大浓度的中位时间为 1.00 至 1.75 小时，并以约 1 小时的几何半衰期下降，在多次给药或更高的单剂量后明显出现较慢的消除阶段（最高测试剂量为 7.1 小时）。平均最大观察浓度（C-max）和血浆浓度与时间曲线下面积（AUC）以剂量成比例的方式增加，并且多次给药后没有蓄积。当在进食状态下给药时，吸收率降低，但总体暴露量没有降低。莫努匹拉韦耐受性良好。不到一半的受试者报告了不良事件，服用安慰剂后不良事件的发生率更高，并且 93.3% 的不良事件是轻微的。一名受试者因皮疹提前停止治疗。没有严重的不良事件，临床实验室、生命体征或心电图也没有发现有临床意义的发现。血浆暴露量超出了根据动物模型的比例得出的预期有效剂量；因此，在达到最大耐受剂量之前停止剂量递增。
Molnupiravir (EIDD-2801/MK-4482), the prodrug of the active antiviral ribonucleoside analog beta-D-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-inhuman, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 h, and declined with a geometric half-life of approximately 1 h, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 h at the highest dose tested). Mean maximum observed concentration (C-max) and area under the plasma concentration versus time curve (AUC) increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of the subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One subject discontinued early due to rash. There were no serious adverse events, and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.