Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, Florida, USA.
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00967-18. Print 2018 Sep.
Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV infection. Favipiravir (FAV) is a viral polymerase inhibitor with broad-spectrum activity. Our prior studies used static FAV concentrations and demonstrated promising activity. However, the anti-ZIKV activity of dynamic FAV concentrations has never been evaluated in a human cell line. Here we employed the hollow-fiber infection model (HFIM) to simulate the human pharmacokinetic (PK) profiles associated with the clinically utilized FAV dosage regimens against influenza and Ebola viruses and assessed the viral burden profiles. Clinically achievable FAV concentrations inhibited ZIKV replication in HUH-7 cells in a dose-dependent fashion (50% effective concentration = 236.5 μM). The viral burden profiles under dynamic FAV concentrations were predicted by use of a mechanism-based mathematical model (MBM) and subsequently successfully validated in the HFIM. This validated, translational MBM can now be used to predict the anti-ZIKV activity of other FAV dosage regimens in the presence of between-patient variability in pharmacokinetics. This approach can be extended to rationally optimize FAV combination dosage regimens which hold promise to treat ZIKV infections in nonpregnant patients.
寨卡病毒（ZIKV）感染与严重的长期神经表现有关。目前尚无针对 ZIKV 感染的治疗或预防的批准疗法。法匹拉韦（FAV）是一种具有广谱活性的病毒聚合酶抑制剂。我们之前的研究使用静态 FAV 浓度并显示出有希望的活性。然而，动态 FAV 浓度的抗 ZIKV 活性从未在人细胞系中进行过评估。在这里，我们使用中空纤维感染模型（HFIM）模拟与临床使用的 FAV 剂量方案相关的人类药代动力学（PK）谱，以评估病毒载量谱。临床可达到的 FAV 浓度以剂量依赖性方式抑制 HUH-7 细胞中的 ZIKV 复制（50%有效浓度=236.5μM）。使用基于机制的数学模型（MBM）预测动态 FAV 浓度下的病毒载量谱，随后在 HFIM 中成功验证。这个经过验证的、转化的 MBM 现在可以用于预测在药代动力学个体间差异存在的情况下其他 FAV 剂量方案的抗 ZIKV 活性。这种方法可以扩展到合理优化 FAV 联合剂量方案，这些方案有望治疗非孕妇的 ZIKV 感染。
