Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection
Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection
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DOI：
10.1016/j.jhep.2014.10.035
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发表时间：
2015-03-01
影响因子：
25.7
通讯作者：
Foster, Graham R.
中科院分区：
文献类型：
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作者：
Agarwal, Kosh;Fung, Scott K.;Foster, Graham R.
背景和目的：替诺福韦艾拉酚胺是替诺福韦的磷酸酯前药，其血浆稳定性高于富马酸替诺福韦二吡呋酯，可在减少全身替诺福韦暴露量的情况下向肝细胞有效递送活性药物。方法：将患有慢性乙型肝炎的非肝硬化、初治受试者随机（1:1:1:1:1）接受替诺福韦艾拉酚胺 8, 25, 40 或 120 mg，或富马酸替诺福韦二吡呋酯 300 mg，持续 28 天，评估安全性、抗病毒反应和药代动力学，停药后随访 4 周。结果：51 名受试者被随机分配，全部完成研究治疗。各组通常与反映人群的 HBV 基因型匹配良好（67% 为男性，57% 为亚洲人，53% HBeAg 阴性，平均 HBV DNA 约为 6.0 log10 IU/ml）。没有受试者经历严重或严重的不良事件（3/4 级）。在替诺福韦艾拉酚胺组中，第 4 周时血清 HBV DNA 的平均变化相似（8、25、40 和 120 mg 组分别为 -2.81、-2.55、-2.19 和 -2.76 log(10) IU/ml），这也与对照组相当（富马酸替诺福韦二吡呋酯为 -2.68 log10 IU/ml） 300 毫克）。各组之间病毒下降的动力学也相似。替诺福韦艾拉酚胺药代动力学呈线性且与剂量成正比；相对于富马酸替诺福韦二吡呋酯 300 mg，625 mg 剂量与平均替诺福韦曲线下面积减少≥ 92% 相关。 结论：艾拉酚替诺福韦是安全的且耐受性良好；在所有评估剂量下，HBV DNA 的下降与富马酸替诺福韦二吡呋酯相似。替诺福韦艾拉酚胺 25 mg 已被选择用于进一步的乙型肝炎临床开发。 (C) 2015 年由 Elsevier B.V. 代表欧洲肝脏研究协会出版。
Background & Aims: Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures.Methods: Non-cirrhotic, treatment-naive subjects with chronic hepatitis B were randomized (1: 1: 1: 1: 1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks.Results: 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log(10) IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses 625 mg were associated with >= 92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg.Conclusions: Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development. (C) 2015 Published by Elsevier B. V. on behalf of the European Association for the Study of the Liver.