Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
Elite Research Institute, Miami, FL, USA.
Clin Pharmacokinet. 2018 Nov;57(11):1449-1457. doi: 10.1007/s40262-018-0645-6.
The 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.
In 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 100 mg. 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/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. 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].
In 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) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant.
No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.
伏西瑞韦是一种强效的全基因型丙型肝炎病毒 NS5A 抑制剂，其药代动力学和安全性在两项肝损伤研究中进行了评估：一项在丙型肝炎病毒未感染者中的 I 期研究和一项在丙型肝炎病毒感染者中的 III 期研究（ASTRAL-4）。
在 I 期研究中，中重度肝损伤（Child-Pugh-Turcotte 分级 B 或 C）患者和匹配的肝功能正常的患者接受单次 100mg 伏西瑞韦治疗。进行了药代动力学和安全性评估，并使用非房室模型方法计算药代动力学参数，并使用描述性统计和几何最小二乘均值比及其 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 分级 B）患者随机接受为期 12 周的索非布韦/伏西瑞韦±利巴韦林治疗或 24 周的索非布韦/伏西瑞韦治疗。进行了药代动力学和安全性评估，并使用非房室模型分析计算药代动力学参数，并使用描述性统计进行总结，并与 ASTRAL-1 （无肝硬化或代偿性（Child-Pugh-Turcotte 分级 A）肝硬化）的药代动力学进行比较。
在 I 期研究中，Child-Pugh-Turcotte 分级 B（n=10）或 Child-Pugh-Turcotte 分级 C 肝损伤患者（n=10）与肝功能正常患者（n=13）相比，血浆暴露量（浓度-时间曲线下面积）相似。无肝损伤或任何程度肝损伤患者的游离伏西瑞韦百分比相似。在 III 期研究中，伏西瑞韦总体暴露量（24 小时给药间隔的浓度-时间曲线下面积；AUC）相似，Child-Pugh-Turcotte 分级 B 肝损伤患者的索非布韦暴露量（约 100%）高于 ASTRAL-1 人群，但认为这无临床意义。
对于任何程度的肝损伤患者，均无需调整索非布韦/伏西瑞韦的剂量。
