ABT378/RITONAVIR WITH RT INHIBITORS IN ANTIRETROVIRAL NAIVE HIV INFECTED PATIENTS

ABT378/利托那韦联合 RT 抑制剂用于抗逆转录病毒治疗初治 HIV 感染患者

• 批准号: 6112800
• 负责人: CHARLES B HICKS
• 金额: $ 4.09万
• 依托单位: DUKE 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/6112800
• 关键词: AIDS therapy; HIV infections; clinical research; drug screening /evaluation; human subject; human therapy evaluation; oral administration; pharmacokinetics; protease inhibitor; ritonavir

Purpose: The main objectives of the study are to assess the safety, tolerability, and antiviral activity of ABT-378/ritonavir and to determine the steady-state pharmacokinetic profile of the combination in healthy, treatment-naive, adult HIV-infected males and females. ABT-378 is an HIV-1 protease inhibitor being developed by Abbott Laboratories which has approximately 10-fold greater in vitro potency than ritonavir and is active against ritonavir-resistant isolates; but ABT- 378 demonstrated poor bioavailability in pre-clinical trials. Co-administration of ABT-378 with ritonavir, however, substantially improves the pharmacokinetic profile of ABT-378. This is attributable to the inhibition of ABT-378 metabolism by ritonavir. Methods: Protocol M97-720 is a Phase I/II, randomized, ABT-378 dose-blinded, multi-center study of oral ABT-378/ritonavir in combination with two marketed reverse transcriptase inhibitor antiretroviral agents [stavudine (d4T) and lamivudine (3TC)] in approximately thirty-two healthy, treatment-naive, adult HIV- infected males and females. On Day -1 patients will be equally randomized to one of two blinded treatment arms: i) 200 mg ABT-378/100 mg ritonavir Q12H and ii) 400 mg ABT-378/100 mg ritonavir Q12H. All patients will add stavudine (d4T) and lamivudine (3TC) to their ABT-378/ritonavir regimen on Day 22. Study drug administration will begin with ABT-378/ritonavir on Study Day 1. All doses of study drug will be directly observed by study personnel (in the GCRC) for Study Days 1-14. After Study Day 14, follow-up visits will be planned for Study Days 16 and 18, Day 21 (Week 3), and Day 28 (Week 4). Following Day 28, visits will be scheduled biweekly until Week 12 and monthly, thereafter. Measurements of vital signs, physical examinations, ECGs, routine clinical laboratory evaluations, determinations of antiviral activity, and quality of life questionnaires will be repeated at regularly scheduled intervals. Blood samples for determination of plasma levels of ABT-378 and ritonavir plasma levels and protein binding will also be obtained. Any patient who discontinues ABT-378/ritonavir will be followed at regularly scheduled study visits for 60 days after the last dose of ABT-378/ritonavir. Results: Twelve male HIV-seropositive subjects have enrolled in the trial. One subject dropped out of the trial after the first visit and has been lost to follow-up. The other eleven subjects have continued to take the study medication and have had increases in CD4 counts and sustained HIV-1 viral suppression below the limits of detection. Two of the eleven subjects have developed some peripheral neuropathy. Four serious adverse events have been reported among the eleven subjects (a mitral valve replacement, a post-surgical ileus, dependence on narcotics, and chest pain, which was found to be gastrointestinal in nature). None of the subjects who experienced serious adverse events had to discontinue the trial, and all have continued to respond well to the study medication. The most common side effects related to the study medication have been loose stools and diarrhea. The most common laboratory abnormalities have been increases in serum cholesterol and triglycerides, which are side effects common to other protease inhibitors. Based on data collected thus far, the study medication appears to be safe, well-tolerated, and effective in suppressing HIV-1 RNA levels below the limits of detection. Significance: Safe, well-tolerated medications that lead to sustained HIV-1 viral suppression to undetectable levels have the potential to decrease stress on the immune system, resulting in higher CD4+ cell counts, longer disease-free survival time, and improved quality of life for people with HIV infection. Future Plans: All subjects in the study will continue to receive study medication beyond the initial 12-month trial, with laboratory evaluation every 3 months. The pharmaceutical sponsor plans to continue to provide the medication to all subjects until either the drug is approved by the FDA or development is discontinued.

目的：本研究的主要目的是评估ABT-378/利托那韦的安全性、耐受性和抗病毒活性，并确定该组合在健康、初治、成人HIV感染男性和女性中的稳态药代动力学特征。ABT-378是由Abbott Laboratories开发的HIV-1蛋白酶抑制剂，其体外效力比利托那韦高约10倍，并且对利托那韦耐药分离株具有活性;但ABT- 378在临床前试验中表现出较差的生物利用度。然而，ABT-378与利托那韦的联合给药显著改善了ABT-378的药代动力学特征。这归因于利托那韦对ABT-378代谢的抑制。研究方法：方案M97-720是一项在约32名健康、未经治疗的成人HIV感染男性和女性中开展的口服ABT-378/利托那韦联合两种市售逆转录酶抑制剂抗逆转录病毒药物[司他夫定（d4 T）和拉米夫定（3 TC）]的I/II期、随机化、ABT-378剂量设盲、多中心研究。在第-1天，患者将被平等地随机分配至两个盲法治疗组之一：i）200 mg ABT-378/100 mg利托那韦Q12 H和ii）400 mg ABT-378/100 mg利托那韦Q12 H。所有患者将在第22天在ABT-378/利托那韦方案中添加司他夫定（d4 T）和拉米夫定（3 TC）。研究药物给药将在研究第1天从ABT-378/利托那韦开始开始。在研究第1-14天，研究人员（在GCRC中）将直接观察所有剂量的研究药物。研究第14天后，计划在研究第16天和第18天、第21天（第3周）和第28天（第4周）进行随访访视。第28天后，计划每两周进行一次访视，直至第12周，此后每月一次。将定期重复测量生命体征、体格检查、ECG、常规临床实验室评价、抗病毒活性测定和生活质量问卷。还将获得用于测定ABT-378血浆水平和利托那韦血浆水平以及蛋白结合的血样。任何停用ABT-378/利托那韦的患者将在ABT-378/利托那韦末次给药后60天的定期计划研究访视中接受随访。结果：12名男性HIV血清阳性受试者入组试验。1例受试者在首次访视后退出试验，失访。其他11例受试者继续服用研究药物，CD 4计数增加，HIV-1病毒抑制持续低于检测限。11例受试者中有2例发生了周围神经病变。在11例受试者中报告了4起严重不良事件（二尖瓣置换术、术后肠梗阻、麻醉剂依赖和胸痛，发现其性质为胃肠道）。发生严重不良事件的受试者均无需终止试验，并且所有受试者均继续对研究药物反应良好。与研究药物相关的最常见副作用是稀便和腹泻。最常见的实验室异常是血清胆固醇和甘油三酯升高，这是其他蛋白酶抑制剂常见的副作用。根据迄今为止收集的数据，研究药物似乎是安全的，耐受性良好，并能有效抑制HIV-1 RNA水平低于检测限。重要性：安全，耐受性良好的药物，导致持续的HIV-1病毒抑制到无法检测的水平，有可能减少对免疫系统的压力，导致更高的CD 4+细胞计数，更长的无病生存时间，并改善艾滋病毒感染者的生活质量。未来计划：研究中的所有受试者将在最初的12个月试验后继续接受研究药物，每3个月进行一次实验室评价。药物申办者计划继续向所有受试者提供药物，直到药物获得FDA批准或开发停止。