Potent Anti-HBV Activity of ACH-126,443

拉米夫定

Potent Anti-HBV Activity of ACH-126,443 Correlated with 14-DAY Pharmacokinetics and Safety Study: Predictions for Activity Against Epivir-HBV-Resistant Mutant Strains The development of novel agents with good safety and favorable resistance profiles are needed for use in combination regimens for the treatment of chronic hepatitis B. ACH-126,443 (ß-L-Fd4C) is an L-nucleoside analog with 10-30 fold greater potency against Hepatitis B virus (HBV) than Epivir (lamivudine;3TC) or Hepsera (adefovir dipivoxil [(ADV]). Results of a Phase 1/II dose-escalating trial of ACH126,443 were presented at the 53rd AASLD in Boston. Following is a summary review of the study abstract: Early clinical pharmacokinetic (PK) data showed excellent oral bioavailability and animal studies showed no significant toxicity associated with plasma levels of several hundred to several thousand ng/mL, 10 to 100-fold higher than predicted for clinical use. In concert with in vitro activity against YMDD mutant HBV strains (IC50<50 ng/mL), these data suggest that, among the currently available HBV drugs, ACH-126,443 may provide potent in vivo activity against the resistant strains, while maintaining a wide safety margin. Methods: This multicenter, blinded, placebo-controlled, ascending-dose, Phase 1/2 trial was designed to evaluate safety, PK and early antiviral activity of 14 days of ACH-126,443 in chronic HBV infection. The study was conducted at 11 centers in North America and Dominican Republic. Thirty-six evaluable treatment-naive HBV-infected subjects were randomized sequentially to dose groups of 1, 5, 10, 20, 50 and 100 mg once daily given orally (5:1 active:placebo per dose group). PK profiles were measured after doses 1 and 14, safety was evaluated weekly during treatment and 2 weeks off therapy. Plasma HBV DNA (Roche COBAS® PCR) was measured bi-weekly during treatment and 2 weeks off therapy. Results: Subjects were 85% male, mean age was 39 years and the patients represented a broad ethnic diversity, including 43% Asian, 33% Caucasian, 10% black and 15% Hispanic. The mean ALT at baseline was 79 IU/mL and the mean plasma HBV DNA level was approximately 7.0 log10. The dose groups were well balanced, as were the placebo recipients within each group. No apparent drug-related adverse events were observed at any dose level. Pharmacokinetic profiles demonstrated peak plasma levels within 1 hour of oral administration 20 ng/mL which exceeded the IC50 of wild-type HBV by 50-fold with doses of 5 mg daily and above. Mean declines of 1.5 - 3.0 log10 plasma HBV DNA, achieved after 14 days of dosing, indicated potent suppression of viral replication in the 5-100 mg daily dose groups (p=0.018 for each active dose group vs placebo). The IC50 of YMDD mutant HBV was reached as a peak plasma drug level with 10 mg daily, and was exceeded by 2 to 20-fold with doses of 20 mg daily and above. No accumulation of free drug was observed in plasma, although sustained viral suppression after discontinuation of treatment with 50 and 100 mg daily suggested that active intracellular ß-L-Fd4C-triphosphate was eliminated more slowly. Conclusions: Studies with other HBV DNA polymerase inhibitors (lamivudine, adefovir) indicate that potent antiviral activity is observed when peak plasma levels meet or exceed the IC50 of the target virus, be it wild-type or YMDD mutant. Oral pharmacokinetics of ACH-126,443 indicate that peak plasma levels well in excess of IC50 of wild-type and YMDD mutant HBV are achieved with low dose levels anticipated to provide a wide safety margin. A Phase 2 trial in 3TC-failing HBV patients is underway; these data will provide support for evaluation of ACH-126,443 in combination regimens for optimal suppression of viral replication. Reference N H Afdhal and others. POTENT ANTI-HBV ACTIVITY OF ACH-126,443 CORRELATED WITH 14-DAY PHARMACOKINETICS AND SAFETY: PREDICTIONS FOR ACTIVITY AGAINST YMDD MUTANT STRAINS.

moonshadow

前几日被拉米兄表扬了一下，士气大振，今天再翻译一篇，人来疯一下！ 大家多指正！：） ACH-126,443具有抗HBV的有效性能 ACH-126,443抗HBV的有效性是与14天的药物动力学和安全性方面的研究相关的：该研究旨在对于能够对付产生了拉米耐药的变异株的能力的预测。 为了使用以治疗慢性B型肝炎为目的的联合疗法，需要开发具有良好安全性和理想耐药反应的新药剂。ACH-126,443 (?-L-Fd4C)是一种L核苷类药物，在抗HBV方面其有效性10－30倍于拉米（Epivir，lamivudine，3TC）或阿德福韦酯（Hepsera，adefovir dipivoxil [(ADV)]。 在波士顿的第53美国肝病学会发布了对ACH126,443进行的1期II阶段扩大剂量试验的结果。以下就是该研究摘要的一个概览。 早期的临床药物动力学（PK）数据显示出了极好的口服生物药效率，而且动物研究显示，在几百到几千ng/ml的血清水平下，与之相关地并未显示出明显的毒性，而该血清水平10－100倍地高于预测的临床用量。 考虑到活体外对抗YMDD变异HBV株(IC50<50 ng/mL)的能力，这些数据提示在现有的可用HBV药物中，ACH-126,443可能在活体内有效地提供抗耐药株的能力，同时维持很高的安全性。 方法：这一1/2期试验具有这些特点：多中心的，盲性的，对照组使用安慰剂，并且剂量递增，设计这个试验的目的是评估ACH-126,443在慢性HBV感染的14天使用中的安全性，药物动力学特性和早期的抗病毒能力。该研究在北美和多美尼加共和国的11个中心进行。 研究人员随机抽取了36例可评估的未经治疗的HBV感染试验对象，将他们分成1, 5, 10, 20, 50 和 100 mg的剂量组并让他们每日口服一次(每一剂量组中治疗组和安慰剂组的比例是5：1)。在第1和第14次服药后测量药物动力学特性，在整个的治疗过程和治疗结束后的两个星期内每周进行一次安全评估。在整个的治疗过程和治疗结束后的两个星期内每两周进行一次血清 HBV DNA(Roche COBAS? PCR)测量。 结果：试验对象中85%为男性，平均年龄为39岁并且患者表现出了广泛的人种差异性，其中包括43%的亚裔，33%的高加索裔，10%的黑人和15%的西班牙裔。其基线平均ALT为79 IU/mL，平均的血清HBV DNA水平大约为7.0 log10。 在每一组中，药剂组和安慰剂组都获得了很好的平衡。在任何一个剂量水平上都没有观察到明显的和药物相关的不利事件发生。 药物动力学特性显示在口服20 ng/mL的剂量后一小时内出现的血清水平的峰值超过每日至少5mg剂量情况下的野生株HBV的IC50（半数细胞抑制剂量）水平的50倍。用药14天后血清HBV DNA平均下降1.5 - 3.0 log10的事实表明在每日5－100mg的剂量组（每一剂量组中治疗和对照的p=0.018）中病毒复制都得到了有效的抑制。 在每日10mg剂量情况下，YMDD变异的HBV的IC50可以作为血清药物水平的峰值而达到，并且在至少每日20mg剂量的情况下可以超过这个水平2到20倍。在每日50和100mg剂量的情况下，治疗终止仍可以保持持续的病毒抑制，这暗示细胞内活跃的?-L-Fd4C-三磷酸盐清除活动变得更加缓慢了。即便如此，在血清中仍观察不到游离药物的积累。 结论：结合其他一些HBV DNA聚合酶抑制剂（拉米呋啶，阿德福韦）的研究显示，当峰值血清水平达到或者超过靶病毒的IC50时，无论是野生株或者YMDD变异株，都可以观察到有效的抗病毒活动。 ACH-126,443的口服药物动力学显示，在预期能够提供很大安全性的条件下，较低的剂量水平能够获得超过野生HBV株和YMDD变异HBV株的IC50相当幅度的峰值血清水平。 针对拉米呋啶（3TC）治疗失败的HBV患者的2期试验正在进行中，这些数据将为评估ACH-126,443在最有效地抑制病毒复制的综合疗法中的使用提供支持。

拉米夫定

以下是引用moonshadow在2003-9-12 18:46:00的发言：
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方法：这一1/2期试验具有这些特点：多中心的，盲性的，对照组使用安慰剂，&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
  

谢谢，感觉您对很多医学词汇的把握还是挺准的。
这个应该译做多通道的、盲性的、安慰剂控制的吧？