AASLD 2013:28天的泰诺福韦富马酸Alafenamide （ TAF）的安全性和有

StephenW

二十八富马酸天的泰诺福韦Alafenamide （ TAF）的安全性和有效性
TITLE: Twenty Eight Day Safety and Efficacy of Tenofovir Alafenamide (TAF) Fumarate in Chronic Hepatitis B (CHB) Patients
AUTHORS (FIRST NAME, LAST NAME): Kosh Agarwal1, Scott K. Fung2, Tuan T. Nguyen3, Wendy Cheng4, Eric Sicard5, Stephen D. Ryder6, John F. Flaherty7, Eileen Lawson7, Sally Zhao7, Mani Subramanian7, John G. McHutchison7, Edward J. Gane8, Graham R. Foster9
Institutional Author(s):
INSTITUTIONS (ALL): 1. Institute of Liver Studies, Kings College Hospital, London, United Kingdom.
2. Toronto General Hospital, Toronto, ON, Canada.
3. T Nguyen Research and Education, San Diego, CA, United States.
4. Royal Perth Hospital, Perth, WA, Australia.
5. Algorithme Pharma, Montreal, QC, Canada.
6. Nottingham University Hospitals NHS Trust and Biomedical Research Unit, Nottingham, United Kingdom.
7. Gilead Sciences, Foster City, CA, United States.
8. Auckland Clinical Studies, Auckland, New Zealand.
9. Queen Mary’s University of London, Barts Health, London, United Kingdom.
ABSTRACT BODY: Background: TAF, an alternate prodrug of tenofovir (TFV), is stable in plasma and more efficiently delivers TFV into lymphoid cells and hepatocytes at lower systemic TFV exposures than tenofovir DF (TDF). In ongoing Phase 2 studies in HIV infection when combined with other antiretrovirals, TAF demonstrated similar efficacy to TDF with less impact on renal function and bone mineral density.
Methods: Prospective, randomized (1:1:1:1:1), open-label, Phase 1b study. CHB subjects with HBV DNA ≥2 x 103 IU/mL and ALT ≤10 x ULN received treatment with TAF at doses of 8, 25, 40, and 120 mg, or TDF 300 mg for 28 days with 4 weeks off-treatment follow-up. Intensive pharmacokinetics (PK) were performed on Day 1.
Results: 51 subjects were enrolled and completed 28 days of dosing. Groups were well matched at baseline (table) and subjects were mostly male and either Asian or Black; 53% were HBeAg-negative. No subject experienced a serious adverse event (SAE), grade 3/4 AE, or discontinued for AE. No subject experienced a renal event (≥0.5 mg/dL increase in creatinine from baseline, phosphorus <2 mg/dL, or CrCL <50 mL/min). The kinetics of reduction in serum HBV DNA were similar across all TAF dose groups and comparable to TDF. PK analysis suggested mean reductions in TFV exposures (AUCinf) of 97%, 93%, 81%, and 32% at TAF doses of 8, 25, 40, and 120 mg, respectively, relative to the mean TFV exposure with TDF.
Conclusions: Over 28 days, TAF was safe and well tolerated. Declines in HBV DNA with TAF did not differ by dose and were similar to TDF. Additionally, TAF may have less impact on renal function (CrCL) compared to TDF. Further clinical trials with TAF are warranted in CHB patients.

StephenW

背景： TAF ，另一种前体药物替诺福韦（ TFV） ，是稳定的血浆和更有效地提供TFV TFV在较低的系统性风险比替诺福韦（ TDF ）进入淋巴细胞和肝细胞。正在进行的第一阶段研究在HIV感染时，与其他抗逆转录病毒药物结合， TAF表现出相似的疗效TDF对肾功能及骨密度的影响较小。
方法：前瞻性，随机（ 1:1:1:1:1 ） ，开放标签，第1b期。慢性乙型肝炎受试者HBV DNA ≥ 2 ×103 IU / mL和ALT ≤ 10× ULN与TAF接受治疗剂量的8 ， 25 ， 40和120毫克，或TDF 300毫克28天，用4周场外治疗随访起来。密集的药代动力学（ PK ）进行第1天。
结果： 51名受试者参加并完成了28天的剂量。组基线匹配（表）的受试者大多是男性和亚洲或黑色的， 53％为HBeAg阴性。没有受试者出现严重不良事件（ SAE ） ， 3/4级曝光，或停产AE 。没有主题经历了肾功能的事件（ ≥0.5 mg / dL的增加，从基线肌酐，磷<2毫克/升，或肌酐清除率<50毫升/分钟） 。降低血清中HBV DNA的动力学是类似在所有TAF剂量组和媲美TDF 。 PK分析表明，平均TFV曝光（ AUCinf ）减少97％ ， 93％ ， 81％ ，和32％在TAF剂量8 ，25 ， 40，和120毫克，分别为，相对于与TDF的平均TFV曝光。
结论：超过28天， TAF是安全的，耐受性好。 HBV DNA下降了TAF没有不同的剂量和类似TDF 。此外， TAF可能有肾功能（肌酐清除率）相比， TDF的影响较小。进一步的临床试验与TAF是必要的慢性乙型肝炎患者。