PHARMACOKINETICS AND ANTIVIRAL EFFECT OF T 20 ADMINISTERED TO HIV 1 ADULTS

T 20 对 HIV 1 成人的药代动力学和抗病毒作用

• 批准号: 6263972
• 负责人: Robert F Murphy
• 金额: $ 2.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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/6263972
• 关键词: AIDS therapy; HIV envelope protein gp41; HIV infections; antiAIDS agent; antiviral agents; clinical research; combination chemotherapy; drug administration routes; drug screening /evaluation; human immunodeficiency virus 1; human subject; human therapy evaluation; nelfinavir; nevirapine; pharmacokinetics; saquinavir; synthetic peptide

Teh observation that resistance has been reported for all of the currently approved antiretroviral HIV agents together with unique toxicities that limit their clinical effectivenss establishes a need for development of new, safe and mechanistically distinct antiviral agents for the treatment of HIV. The investigational agent, T-20 , is a 36-amino acid synthetic peptide. T-20 is a linear moecule composed of naturally occurring 1-amino acid residues. The pirmary sequence of T-20 was derived from a naturally occurring motif (amino acid residues 643-678) within gp41 transmembrane glycoprotein of HIV-1. The results of nonclinical mechanism of action studies indicate that T-20 exhibits potent and selective inhibition of de novo infection and cell to cell virus transmission by binding to a critical region of gp41 which regulates the fusion of virus to host cell membranes. Nonclinical safety studies conducted in rodents and primates indicate that the intravenous administration of T-20 twice daily for 28 consecutive days is not associated with any markers of either clinical or laboratory toxicity. This trial will be studying the safety, pharmacokinetics, and antiviral activity of T-20 given by continuous subcutaneous injection to HIV-1 positive adults with HIV-RNA levels greater than 5,000 copies/ml and who have been treated with a 3-drug antiviral regimen containing 2 nucleoside reverse transcriptase inhibitors and indinavir. During this study, the patient will be randomized to receive treatment with one of four dose levels of T-20 alone by continuous subcutaneous infusion (CSI) or one dose level by intermittent subcutaneous injection ten days and then he/she will receive T-20 by CSI along with nevirapine, nelfinavir, and saquinavir for approximately 24 weeks.

已经报道了对所有目前批准的抗逆转录病毒HIV药物的耐药性以及限制其临床有效性的独特毒性，这一观察建立了开发用于治疗HIV的新的、安全的和机制上不同的抗病毒剂的需要。 研究药物T-20是一种由36个氨基酸组成的合成肽。 T-20是由天然存在的1-氨基酸残基组成的线性分子。 T-20的原序列来源于HIV-1的gp 41跨膜糖蛋白内天然存在的基序（氨基酸残基643-678）。 非临床作用机制研究的结果表明，T-20通过与调节病毒与宿主细胞膜融合的gp 41关键区域结合，对从头感染和细胞间病毒传播表现出强效和选择性抑制作用。在啮齿类动物和灵长类动物中进行的非临床安全性研究表明，连续28天每天两次静脉给予T-20与任何临床或实验室毒性标志物无关。本试验将研究T-20持续皮下注射给药的安全性、药代动力学和抗病毒活性，受试者为HIV-1阳性成人，HIV-RNA水平大于5，000拷贝/ml，且已接受含2种核苷逆转录酶抑制剂和茚地那韦的3种药物抗病毒方案治疗。 在本研究期间，患者将随机接受连续皮下输注（CSI）4个剂量水平之一的T-20单独治疗或间歇皮下注射1个剂量水平治疗10天，然后他/她将接受T-20 CSI沿着奈韦拉平、奈非那韦和沙奎那韦治疗约24周。