Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses
Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses
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DOI：
10.1128/aac.01305-16
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发表时间：
2017-01-01
影响因子：
4.9
通讯作者：
Raoul, Herve
中科院分区：
文献类型：
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作者：
Madelain, Vincent;Guedj, Jeremie;Raoul, Herve
Favipiravir是一种RNA聚合酶抑制剂，在体外和对几种导致出血热（HF）的病毒（包括埃博拉病毒）的小动物模型中显示出很强的抗病毒功效。这项工作的目的是表征非人灵长类动物（NHPs）中favipiravir的复杂药代动力学，以指导未来favipiravir在大型动物模型中的疗效研究。在中国（n = 17）或毛里求斯（n = 13）的30只未感染食蟹猕猴（n = 13）中进行了四项不同的研究，静脉注射法匹拉韦7至14天，维持剂量为60至180 mg/kg体重，每天两次（BID）。建立了一个药代动力学模型来预测不同给药方案获得的血浆浓度，并将模型预测与favipiravir对几种病毒的50%有效浓度（EC50）进行了比较。采用浓度依赖性醛氧化酶抑制模型描述了法匹拉韦的药代动力学。酶依赖的消除率随着时间的推移而增加，毛里求斯血统的NHPs比中国血统的NHPs更高。预计中国和毛里求斯NHPs维持剂量分别为100和120 mg/kg BID，可在第7天达到拉沙和马尔堡病毒血浆游离浓度高于EC50的中位谷值。对于埃博拉病毒，需要更高的剂量。第7天之后，需要增加20%的剂量来补偿随着时间的推移而增加的药物清除率。这些结果将有助于在未来评估favipiravir在NHPs中的抗病毒作用的研究中合理选择给药方案，并支持其针对多种HF病毒的开发。
Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.