PHASE II SEQUENTIAL COHORT 3 DOSE LEVELS OF ORAL ADEFOVIR DIPIVOXIL

口服阿德福韦酯的 II 期序贯队列 3 剂量水平

• 批准号: 6114401
• 负责人: PATRICIA A BARDITCH-CROVO
• 金额: $ 2.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6114401
• 关键词: antiviral agents; chronic disease /disorder; clinical research; drug screening /evaluation; hepatitis B; hepatitis B virus group; human subject; human therapy evaluation; liver disorder chemotherapy; nucleoside analog; oral administration; transaminases

Chronic hepatitis B virus (HBV) continues to be an important worldwide cause of morbidity, mortality and source of potential new infections. There are estimated to be 300 million carriers of HBV in the world. Interferon alpha-2b is the only drug approved for the treatment of chronic HBV. Long term suppression of virus has only been accomplished in 25-50% of people receiving interferon. Furthermore many are unable to tolerate the drug because of side effects. Therefore effective and safe new agents for the treatment of hepatitis B infection are needed. Adefovir (PNMA or 9-[2-(phosphonomethoxy)ethyl]adenine) is a broad spectrum nucleotide analog with in vitro and in vivo activity against hepadnaviruses, retroviruses, and herpesviruses. It also has activity against duck (DHBV) and human hepatitis B (HBV) in vitro and in animal models. Adefovir dipivoxil, also known as bis-POM PMEA; is an orally available prodrug of adefovir (PMEA). In the DHBV model of infection, adefovir was found to be active in both hepatic and extrahepatic sites, such as bile ducts and the pancreas, with reductions in DHBV markers. When administered at a daily dose of 120 mg to 15 HBV-infected people for four weeks, adefovir dipivoxil was associated with rapid and significant declines in serum HBV DNA levels. Elevations in liver transaminases were noted in participants receiving active drug. After termination of dosing, HBV DNA levels returned to baseline over on to six weeks in active drug recipients. Due to the potent antiviral activity observed in this initial trial, further study of this drug in patients with chronic HBV is proposed. As part of a multicenter trial, we plan to study adefovir dipivoxil at lower doses (30, 60 mg/day) in addition to the dose previously evaluated (120 mg/day). Subjects will receive drug daily for 12 weeks in order to further evaluate the safety, tolerance and anti-HV activity of adefovir dipivoxil.

慢性B型肝炎病毒（HBV）仍然是世界范围内的重要疾病， 发病原因、死亡原因和潜在新感染源。 据估计，全世界有3亿HBV携带者。 干扰素α-2b是唯一被批准用于治疗 慢性HBV。 长期抑制病毒的工作 在25-50%接受干扰素治疗的患者中。 此外，许多人无法 因为药物的副作用因此，有效和 需要用于治疗B型肝炎感染的安全的新药剂。 阿德福韦（PNMA或9-[2-（膦酰甲氧基）乙基]腺嘌呤）是一种广泛的 具有体外和体内抗肿瘤活性谱核苷酸类似物 嗜肝DNA病毒、逆转录病毒和疱疹病毒。 它还具有活性 鸭乙型肝炎病毒（DHBV）和人乙型肝炎病毒（HBV）的体外和动物试验 模型 阿德福韦酯，也称为双-POM PMEA;是一种口服给药制剂， 阿德福韦酯的前体药物（PMEA）。 在DHBV感染模型中， 发现阿德福韦在肝和肝外部位都有活性， 如胆管和胰腺，DHBV标志物减少。 当15名HBV感染者每天服用120 mg时， 四周内，阿德福韦酯与快速和 血清HBV DNA水平显著下降。 肝脏升高 在接受活性药物的参与者中观察到转氨酶。 后 给药结束后，HBV DNA水平恢复至基线水平， 在活跃的药物接受者中六周。 由于在该初步试验中观察到的有效抗病毒活性， 建议对该药物在慢性HBV患者中的进一步研究。 作为多中心试验的一部分，我们计划在 除先前评价的剂量外，还可使用较低剂量（30、60 mg/天） (120 mg/天）。 受试者将每天接受药物治疗，持续12周， 进一步评价安全性、耐受性和抗HV活性， 阿德福韦酯