Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC₅₀ in vivo to 2.89 μg.mL^-1, which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.

拉沙热是由拉沙病毒（LASV）引起的出血热。尽管疗效证据有限，但尚无针对LASV的疫苗被批准，并且唯一推荐的抗病毒治疗依赖于利巴韦林。最近，核苷酸类似物favipiravir表现出很高的抗病毒效力，在拉萨热原本完全致命的非人灵长类动物（NHP）模型中获得了100％的存活率。但是，该药物的作用机理尚不清楚，并且缺少药代动力学数据也限制了这些结果向人类环境的转化。在这里，我们旨在通过开发第一个概括拉萨病毒动力学和治疗方法的数学模型，更好地了解法维吡韦的抗病毒作用。我们分析了未经治疗或未用利巴韦林或法维拉韦治疗的24种NHP中的病毒动力学，并且我们将结果与在埃博拉病毒感染情况下使用相同药物获得的结果进行了比较。我们的模型估算出favipiravir EC₅₀ 体内，以2.89 μ g.mL ^-1，这是更比被发现针对埃博拉病毒的降低。法维吡韦的主要作用机制是降低病毒的感染性，最高剂量时的功效为91％。根据我们对人类药物药代动力学的了解，我们的模型预测，每天两次大于1200 mg的favipiravir剂量应具有强烈减少生产传染性病毒的能力，并为人类未来使用提供里程碑。