GS-7340和其他抗逆转录药物合用在血液中效果强于泰诺福韦

肝胆速递

GS-7340 Stronger Than TDF in Human Serum, Synergistic With Other ARVs
GS-7340和其他抗逆转录药物合用在血液中效果强于泰诺福韦

肝胆速递：泰诺福韦的前体药物GS-7340（Gs-7340经人体代谢后转变为泰诺福韦）和其他抗逆转录药物合用在血液中抗HIV效果强于泰诺福韦，原因是GS-7340在血液中更稳定

52nd ICAAC, September 9-12, 2012, San Francisco

Mark Mascolini

GS-7340, the investigational oral prodrug of tenofovir, had stronger antiviral activity than tenofovir disoproxil fumarate (TDF) in vitro in the presence of human serum [1]. The new agent was additive to synergistic with other antiretrovirals, including the three non-TDF components of QUAD.

TDF, the widely used reverse transcriptase inhibitor, and GS-7340 (tenofovir alafenamide, TAF) are both prodrugs of tenofovir, which is metabolized inside cells to the active metabolite tenofovir diphosphate. Because GS-7340 is more stable in human serum than TDF, it may hold advantages over TDF. Research in humans indicates that GS-7340 achieves enhanced delivery of tenofovir to the lymphatic system, higher intracellular concentrations of tenofovir, greater viral load suppression at doses lower than TDF, and lower circulating tenofovir levels, which may improve safety and tolerability [2,3].

Gilead Sciences investigators evaluated the antiviral activity of GS-7340 against HIV-1 and HIV-2 isolates in peripheral blood mononuclear cells and against a panel of other human viruses. These experiments showed that GS-7340 had high potency against 26 HIV-1 isolates representing 7 subtypes, averaging a 50% effective concentration (EC50) of 3.6 nM. GS-7340 had an average EC50 of 1.8 nM against three HIV-2 isolates.

While antiviral potency of TDF was significantly reduced in the presence of human serum, GS-7340 maintained its antiviral potency after prolonged serum exposure, a finding consistent with the greater stability of GS-7340 than TDF in plasma.

The investigational prodrug had no significant activity against other viruses studied, including CMV, HSV-1, or VZV. It had moderate activity against HSV-2.

When combined with other antiretrovirals and with the boosting agent cobicistat, GS-7340 had strong synergistic activity with emtricitabine (FTC), elvitegravir, raltegravir, and dolutegravir and moderately synergistic activity with efavirenz, atazanavir, and darunavir. GS-7340 had slight synergy or was additive with tenofovir, nevirapine, and cobicistat. No antagonist interactions with other agents were identified. If development of GS-7340 proceeds smoothly, Gilead will probably coformulate it with elvitegravir, cobicistat, and FTC in a second-generation QUAD.

The Gilead team concluded that GS-7340 "has a virological profile similar to that of tenofovir regarding spectrum of activity." But the investigational agent had stronger antiviral activity than TDF in the presence of human serum, "consistent with the higher intracellular tenofovir diphosphate levels and greater antiviral potency seen in the clinical setting as compared to TDF."

One question always arises after GS-7340 penetrations: Does the drug's better cell penetration compared with TDF mean it will heighten toxicity in kidney and bone cells? Christian Callebaut, who presented these Gilead findings, said studies in kidney cells disclosed no evidence of heightened toxicity, while studies in bone cells are under way.

References
1. Callebaut C, Margot N, Stepan G, Tian T, Miller M. Virological profiling of GS-7340, a next-generation tenofovir prodrug with superior potency over TDF. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-552.
2. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103. http://www.natap.org/2012/CROI/croi_29.htm.
3. Markowitz M, Zolopa A, Ruane P, et al. GS-7340 Demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 152LB.

肝胆速递

主题：NATAP / ICAAC：GS-7340

GS-7340更强有力比TDF人血清中，与其他抗逆转录病毒药物的协同的

9月9-12日第52届ICAAC 2012年，旧金山

马克Mascolini

在人血清[1]的存在下，GS-7340，在体外研究口服前药的替诺福韦，有更强的抗病毒活性比替诺福韦disoproxil富马酸（TDF）。新的代理添加剂的协同与其他抗逆转录病毒药物，包括非TDF三个组成部分的四。

TDF的，广泛使用的逆转录酶抑制剂，和GS-7340（替诺福韦alafenamide，TAF）都替诺福韦，前药的细胞内代谢成活性代谢物替诺福韦二磷酸。由于GS-7340更稳定，比TDF人血清中，它可容纳超过TDF的优势。在人类的研究表明，GS-7340达到增强替诺福韦交付到淋巴系统，替诺福韦较高的细胞内浓度，剂量低于TDF更大的病毒载量的抑制，和下部循环替诺福韦水平，这样可以提高安全性和耐受性[2,3 。

Gilead Sciences公司研究人员评估了GS-7340对HIV-1和HIV-2分离的外周血单个核细胞，对一组的其他人类病毒的抗病毒活性。这些实验表明，GS-7340对26 HIV-1分离株，占7亚型，具有较高的效价平均为50％有效浓度（EC50）为3.6纳米。 GS-7340对HIV-2菌株的平均EC50为1.8 nm。

虽然抗病毒效力的TDF显着减少在人血清存在下，血清经过长时间的曝光，TDF GS-7340比血浆中的更大的稳定性的发现相一致，GS-7340保持其抗病毒效力。

该研究的前体药物没有显着的活性，对其他病毒的研究，包括CMV，HSV-1，VZV。它有中等强度的运动对HSV-2。

当结合与其他抗逆转录病毒药物和促进剂cobicistat的，GS-7340具有强大的协同活动与恩曲他滨（FTC），elvitegravir，拉替拉韦和dolutegravir和依非韦伦，阿扎那韦，darunavir的适度的协同活动。 GS-7340有轻微的协同作用或者，添加剂与替诺福韦，奈韦拉平，cobicistat的。没有阻断剂与其他药物的相互作用进行了鉴定。如果GS-7340进行开发的顺利进行，Gilead公司可能会coformulate与elvitegravir，cobicistat，FTC的第二代四。

基列小组得出结论，GS-7340“一个病毒学替诺福韦有关频谱的活动类似。”但是，研究药物在人血清存在下，具有较强的抗病毒活性比TDF“一致的较高的细胞内替诺福韦二磷酸水平和在临床上看到更大的抗病毒效力相比，TDF。”

有一个问题总是出现后，GS-7340穿透药物的细胞渗透是否意味着它会提高在肾脏和骨细胞的毒性相比，TDF？基督教百乐嘉利宝，谁提出这些Gilead公司的调查结果说，肾细胞的研究宣称没有高度毒性的证据，而骨细胞的研究正在进行中。

参考文献
1。斯捷潘·玛戈Ň，百乐嘉利宝C，G，田T，M.米勒病毒学分析，GS-7340，新一代的替诺福韦具有超强的前体药物效力过TDF。第52届跨领域抗生素和化疗会议（ICAAC）。 9月9-12日2012年。旧金山。文章摘要H-552。
2。 Ruane P，德吉泽斯Ë，D伯杰ð等。 GS-7340 25毫克和40毫克富马酸替诺福韦酯300毫克，一个10天的单药治疗的HIV-1（+）患者的研究表现出卓越的疗效。第19次逆转录病毒和机会性感染。 2012年3月5-8日。西雅图。摘要103。 http://www.natap.org/2012/CROI/croi_29.htm。
3。马可维茨M，P，A，Ruane Zolopa等。 GS-7340演示比TDF在HIV-1 RNA的幅度更大，在14天的单药治疗的HIV-1感染者。第18次逆转录病毒和机会性感染。 2月27日至3月二日，2011年。波士顿。摘要152LB。

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