Esmaeili Shadisadat, Owens Katherine, Standing Joseph F, Lowe David M, Zhang Shengyuan, Watson James A, Schilling William H K, Wagoner Jessica, Polyak Stephen J, Schiffer Joshua T
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center; Seattle, WA, USA.
Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK.
medRxiv. 2025 Jan 6:2024.11.21.24317726. doi: 10.1101/2024.11.21.24317726.
Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 7-8 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.5 log in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.
莫努匹韦是一种抗病毒药物，在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）RNA复制过程中引发致命的复制错误。在一项关键试验中，莫努匹韦将住院率降低了50%，并且在三项独立试验中对降低病毒RNA水平有不同效果。我们使用数学模型来模拟这些试验，并精确重现了它们的病毒学结果。模型模拟表明，与针对奥密克戎毒株相比，对奥密克戎之前的SARS-CoV-2变体的抗病毒效力较低。我们估计，体外试验对奥密克戎变体的体内效力低估了7至8倍。我们的模型表明，由于聚合酶链反应检测到莫努匹韦突变的变体，在奥密克戎变体占主导的两项试验中，未突变病毒RNA的真实减少量被低估了约0.5个对数。未突变和突变病毒RNA的曲线下面积估计值有显著差异。我们的结果强化了过去的研究工作，表明体外试验在估计体内抗病毒药物效力方面不可靠，并表明呼吸道病毒临床试验的病毒学终点应根据药物作用机制进行调整。
