Favipiravir (T-705; 6-fluoro-3‑hydroxy-2-pyrazinecarboxamide) is an orally bioavailable nucleoside analog that selectively inhibits the PB1 subunit of the RNA-dependent RNA polymerases of influenza with activity against a range of other RNA viruses[1]. Favipiravir has been studied in humans initially for influenza and subsequently for emerging pathogens, including Ebola and COVID-19.

法维拉韦（T-705； 6-氟-3-羟基-2-吡嗪甲酰胺）是一种口服的核苷类似物，可选择性抑制流感RNA依赖聚合酶的PB1亚基，并具有针对其他多种RNA病毒的体外活性[1]。法维拉韦最初研究用于流感治疗的临床试验，随后又用于其他新发突发传染病的试验，包括埃博拉和COVID-19。

For Ebola, high doses of favipiravir was utilized (day 0: 6000 mg; day 1 to day 9: 2400 mg/d) in an open-label observational study [2]. The dosing was selected to result in target time-weighted average plasma concentration (Cave_u) to be 52 μg/ml. While therapy was generally well tolerated, mortality was not different from patients who received similar standard of care alone. Unfortunately, despite the high doses, favipiravir concentrations did not result in steady state accumulations (day 2: 46.1 µg/mL (23–106.9); day 4: 25.9 µg/mL (0–173.2), median (range)) seen with typical first-order elimination drugs. No correlation between plasma concentration and decline in Ebola viral load in plasma or mortality was found.

对于埃博拉病毒，在开放标签的观察性研究中使用了大剂量的法维拉韦（第0天：6000mg；第1天至第9天：2400mg / d）[2]。选择剂量以使目标时间加权平均血浆浓度（Cave_u）为52μg/ ml。尽管通常对治疗的耐受性良好，但死亡率与仅接受类似护理标准的患者并无不同。不幸的是，尽管高剂量，但法维拉韦浓度并未达到稳态积累（第2天：46.1µg / mL（23-106.9）；第4天：25.9µg / mL（0-173.2），单位为中位数（范围））典型的一级消除药物。血浆浓度与血浆埃博拉病毒载量下降或死亡率之间无相关性。

Given in vitro data against SARS-CoV-2 and the ability to dose orally, there has been interest in the use of favipirivir for the treatment of COVID-19. In the first study, 3 arms (1800 mg BID x 2 doses then 800 mg BID (high dose) vs. 1600 mg BID x 2 doses then 600 mg BID (low dose) vs. placebo) were studied in hospitalized COVID-19 patients in Russia. Favipiravir was associated with more rapid clearance of PCR and resolution of fever [3]. In the second open-label study, 89 Japanese patients were randomized to early vs late therapy for asymptomatic or mild COVID-19 using high dose favipirivir. Therapy was not associated with a difference in viral clearance (n = 69 evaluable patients) or a trend to faster defervescence (n = 30 evaluable patients) [4]. In the last study, 156 Japanese hospitalized COVID-19 patients were randomized to receive high dose favipirivir vs. placebo. Favipiriavir was associated with more rapid alleviation of symptoms and PCR negativity (11.9 vs. 14.7 days) [5]. None of the studies included PK assessments of favipiravir.

鉴于抗SARS-CoV-2的体外数据和口服剂量的耐受性，大家一直对使用法维拉韦治疗COVID-19十分感兴趣。在俄罗斯开展的法匹拉韦治疗新冠的一项研究中，对住院的COVID-19患者研究了3组（分别为1800mg BID x 2剂量然后800mg BID（高剂量）与1600mg BID x 2剂量然后600mg BID（低剂量）与安慰剂），法维拉韦与病毒PCR快速清除和发烧消退相关[3]。在第二项开放标签研究中，将89例日本患者随机分为两组，分别采用高剂量法维拉韦进行无症状或轻度COVID-19的早期和晚期治疗。治疗与病毒清除率的差异（n = 69名可评估患者）或退热更快的趋势（n = 30名可评估患者）无关[4]。在最近的研究中，将156例日本住院的COVID-19患者随机分配接受大剂量的非那韦利治疗与安慰剂治疗。 法维拉韦与症状的快速缓解和PCR阴性（11.9比14.7天）相关[5]。但没有一项研究包括法维拉韦的PK评估。

Clinical trials of favipiravir in uncomplicated influenza studied doses from 1600 to 1800 mg BID on day 1 then 600mg-800 mg BID on day 2–5 (NCT02026349, NCT02008344) [1]. Both trials showed a significant antiviral effect and more rapid symptom resolution. The drug was well tolerated except for transient asymptomatic elevations in uric acid. These and other data led to the approval of favipiravir in 2014 in Japan for the treatment of novel influenza strains.

法维拉韦在治疗单纯性流感的临床试验中研究剂量是从第1天负荷剂量1600到1800mg BID，在第2-5天维持剂量600mg到800mg BID（NCT02026349，NCT02008344）[1]。两项试验均显示出显着的抗病毒作用和更快的症状缓解。除尿酸短暂无症状升高外，该药物耐受性良好。这些数据和其他数据使得法维拉韦于2014年在日本获得批准用于治疗新型流感病毒株。

The CAP-China Network presents data from an study to define PK and outcomes of favipiravir plus oseltamivir in patients ≥18 years of age severely ill (respiratory failure, defined as having a PaO2/FiO2 ≤300 mmHg or receiving mechanical ventilation) with PCR-confirmed influenza [6]. In this dose-ranging study, 16 severely ill patients received 1600 mg BID on day 1 and 600 mg BID while 19 received 1800 mg BID on day 1 and 800 mg BID; all patients received oseltamivir 75 mg BID; both drugs were given for a total of 10 days. Sparse trough and/or peak blood sample collection was planned (doses 1, 3, 5, 13, and 19) with patients randomized to have additional blood samples on dose 1, 3, and 20. The authors fit a compartmental model with first-order absorption and clearance, with the latter modified by a linear increase in clearance over time. The authors’ selected primary PK endpoint, favipiravir Ctrough ≥20 mg/L after the second dose, was not achieved in either dosing group. Favipiravir Ctrough decreased significantly over time in both groups (p80% of the duration of treatment. There was no association between maintaining Ctrough ≥20 mg/L on day 3 and a reduction in viral loads. Their simulations suggested that a loading dose of ≥ 3600 mg BID for the first day followed by 2600 mg BID for remaining doses would be needed to achieve a target Ctrough for the duration of treatment. It is important to note, however, that their model fit was limited by a sparse sampling design and led to shrinkage estimates of 49.2% and 53.4% for the between-subject variation of Ka and V, respectively. With shrinkage numbers that exceed 30%, caution should be exercised as the model internal validity exceeds the external predictive capacity (such as with simulations) [7]. Their suggested doses, while within the range of that used in Ebola trials, should be considered with extreme caution in COVID-19 as adverse event profiles are very unclear with this dosing paradigm [8,9].

中国肺炎研究网（CAP-China）的一项研究揭示了法维拉韦和奥司他韦 PK数据，该研究纳入了PCR确诊的18岁以上重症流感患者（呼吸衰竭，指PaO2 / FiO2≤300mmHg或接受机械通气） [6]。在这项剂量范围研究中，有16名重症患者在第1天接受1600mg BID和600mg BID，而19位在第1天接受1800mg BID和800mg BID；所有患者均接受奥司他韦75mg BID；两种药物共给药10天。计划进行稀疏谷和/或峰值血样采集（剂量1、3、5、13和19），并随机分配患者在剂量1、3和20时采集更多血样。作者采用了一级吸收和清除的房室模型，清除量校正为随时间线性增加而改变。作者选择的主要PK终点为：第二次个给药后达到或未达到法维拉韦Ctrough（谷浓度）≥20mg / L的人数比例。两组的法维拉韦Ctrough随时间均显着下降（p