A pharmacokinetic/viral kinetic model to evaluate treatment of chronic HCV infection with a non-nucleoside polymerase inhibitor.
A pharmacokinetic/viral kinetic model to evaluate treatment of chronic HCV infection with a non-nucleoside polymerase inhibitor.
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DOI：
10.3851/imp3216
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发表时间：
2018
影响因子：
1.2
通讯作者：
Perelson AS
中科院分区：
文献类型：
--
作者：
Canini L;Lemenuel-Diot A;Brennan BJ;Smith PF;Perelson AS
病毒动力学模型已被证明可用于表征干扰素 (IFN) 以及直接作用抗病毒药物 (DAA) 治疗 HCV 期间的治疗效果。在这里，我们使用药代动力学/病毒动力学 (PK/VK) 模型来描述用司曲布韦（HCV NS5B 聚合酶的非核苷抑制剂）治疗期间的 HCV RNA 动力学。使用来自健康志愿者的 3 项研究的 PK 数据以及来自 1 期研究的 PK 和 VK 数据（其中司曲布韦给药 3 天），我们拟合了具有一级吸收和滞后时间的双室 PK 模型、Emax 药效学模型和标准双相病毒动力学模型。感染HCV亚型1b和1a的患者之间塞曲布韦的EC50和Hill系数以及病毒清除率存在显着差异（分别为P=0.014、P<0.001和P=0.004），导致感染基因1b病毒的患者病毒载量下降幅度更大。了解 PK/VK 对非核苷聚合酶抑制剂（如司曲布韦）性能的综合影响，可以为它们与其他 DAA 的联合使用以及优化未来的治疗提供有价值的见解。此外，我们的工作表明，感染 1a 亚型的患者需要比感染 1b 亚型的患者更高的剂量才能达到相同的效果。需要检查其他非核苷聚合酶抑制剂是否也是如此。
Viral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct acting antivirals (DAAs). Here we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from 3 studies in healthy volunteers and PK and VK data from a phase 1 study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic viral kinetic model. Setrobuvir’s EC50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus. Understanding the combined effects of PK/VK on the performance of a nonnucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.