Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment
Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment
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DOI：
10.1007/s40262-018-0645-6
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发表时间：
2018-11-01
影响因子：
4.5
通讯作者：
Mathias, Anita
中科院分区：
文献类型：
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作者：
Mogalian, Erik;Brainard, Diana M.;Mathias, Anita
背景在两项肝损害研究中评估了维帕他韦（一种强效泛基因型丙型肝炎病毒NS 5A抑制剂）的药代动力学和安全性：在未感染丙型肝炎病毒的受试者中进行的I期研究和III期研究方法在I期研究中，中度或重度肝损害的受试者，（Child-Pugh-Turcotte分级B或C），人口统计学匹配的肝功能正常的受试者接受单剂量的维帕他韦100 mg。进行药代动力学和安全性评估，使用非房室方法计算药代动力学参数，使用描述性统计量进行总结，并通过几何最小二乘均值比和90%置信区间进行统计学比较。在ASTRAL-4中，失代偿性肝硬化（Child-Pugh-Turcotte B级）受试者随机接受索非布韦/维帕他韦利巴韦林治疗12周或索非布韦/维帕他韦治疗24周。进行药代动力学和安全性评估，使用非房室分析计算药代动力学参数，并使用描述性统计量进行总结，并与ASTRAL-1 [无肝硬化或代偿性肝硬化受试者]的药代动力学进行比较。（Child-Pugh-Turcotte A级）肝硬化]。结果在I期研究中，血浆暴露Child-Pugh-Turcotte B级（n=10）或Child-Pugh-Turcotte C级肝损害（n=10）受试者的浓度-时间曲线下面积相似与肝功能正常组（n=13）比较。在无或有任何程度肝损害的受试者中，游离维帕他韦的百分比相似。在III期研究中，维帕他韦的总暴露量（24小时给药间隔内的浓度-时间曲线下面积; AUC（tau））相似，索非布韦暴露量较高与ASTRAL-1人群相比，Child-Pugh-Turcotte B级肝功能损害患者中，这是不被认为是临床relevant.ConclusionsNo索非布韦/维帕他韦剂量调整是必要的患者有任何程度的肝损害。
BackgroundThe pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients.MethodsIn the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvirribavirin for 12weeks or sofosbuvir/velpatasvir for 24weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis].ResultsIn the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n=10) or Child-Pugh-Turcotte Class C hepatic impairment (n=10) compared with normal hepatic function (n=13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUC(tau)) was similar and sofosbuvir exposures were higher (similar to 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant.ConclusionsNo sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.