Clinical safety and pharmacokinetic studies of intravaginal rings releasing multiple antiretrovirals

 描述（由申请人提供）：该项目的目标是防止艾滋病毒传播。使用我们为更昔洛韦眼内植入物Vitrasert开发的药物递送平台，我们建议开发一种阴道环（IVR），释放抗逆转录病毒药物替诺福韦、恩曲他滨和马拉韦罗。选择这种药物组合是因为其效力、协同作用和耐药性预防。选择替诺福韦和恩曲他滨的理由非常充分：这些是Truvada（r）中的药物，并在HIV传播的临床研究中证明了疗效。Maraviroc已证明可在猕猴中预防SHIV传播。在NIAID的R21、R33和SBIR赠款的部分资助下，我们成功地改造了Vitrasert（r）平台，并在多种动物模型中安全地提供了多种抗逆转录病毒药物。该SBIR项目I期的目标是进行必要的临床前工作，以获得FDA研究性新药豁免（IND），从而在临床研究中测试该制剂。这一里程碑已经实现：IND 123099已获得FDA批准。第二阶段SBIR提案的目标是进行首次人体研究。释放单一药物和组合药物的环将由正常志愿者佩戴7天。安全性将通过阴道镜检查和我们开创的新型超声程序，以及细胞因子测量和微生物组评估来确定。将通过在局部组织和体液以及血浆中随时间推移的测量来确定药代动力学。7天研究完成后，将有一个洗脱期，并将数据提交给FDA。如果在戴环7天后没有安全性问题，则将在28天内重复研究。后续SBIR III期研究计划在非洲人群中进行。开发一种有效的杀微生物剂IVR每年可以挽救数百万人的生命，因此具有非常重要的意义。我们相信我们是唯一有资格开发这样一种产品的公司，我们的戒指展示了对当前最先进技术的巨大改进。研究人员团队是化学、药代动力学、工程、妇科临床试验和药物开发方面的专家，我们在药物开发过程的各个方面都有经验，从概念到批准和营销。该提案的里程碑将是成功完成该临床试验，证明药物的安全性和局部给药足以值得进一步的临床试验，以寻求FDA批准和临床实施。这项工作的成功完成之后，将进行研究和计划，以大规模制造这些环，并进行最终批准所需的临床试验。作为唯一FDA批准的持续释放抗病毒药物输送装置的开发商，我们相信我们是唯一有资格进行这样一个雄心勃勃的计划。

 DESCRIPTION (provided by applicant): The goal of this project is to prevent HIV transmission. Using the drug delivery platform that we developed for the ganciclovir intraocular implant, Vitrasert(r), we propose to develop an intra-vaginal ring (IVR) releasing the antiretrovirl agents tenofovir, emtricitabine and maraviroc. This drug combination has been chosen for potency, synergistic action, and the prevention of resistance. The rationale for the choice of tenofovir and emtricitabine is very strong: these are the drugs in Truvada(r) and have demonstrated efficacy in clinical studies of HIV transmission. Maraviroc has demonstrated protection against SHIV transmission in macaques. Funded in part by R21, R33, and SBIR grants from the NIAID, we have successfully adapted the Vitrasert(r) platform and safely delivered multiple antiretrovirals in multiple animal models. The goal of Phase I of this SBIR project was to perform the necessary pre-clinical work for allowance of an FDA Investigational New Drug Exemption (IND) to test this formulation in a clinical study. This milestone has been achieved: IND 123099 has been allowed by the FDA. The goal of this Phase II SBIR proposal is to carry out this first in human study. Rings releasing single drugs and combinations will be worn by normal volunteers for 7 days. Safety will be determined by colposcopy and a novel ultrasound procedure which we pioneered, as well as cytokine measurements and assessments of the microbiome. Pharmacokinetics will be determined by measurement over time in local tissues and fluids, as well as in plasma. On completion of the 7 day study there will be a washout period and the data will be presented to the FDA. If there are no safety concerns after wearing the ring for 7 days, the study will be repeated over a 28 day period. Subsequent SBIR Phase III studies are planned in African populations. The development of an effective microbicide IVR could save millions of lives per year and is therefore highly significant. We believe we are uniquely qualified to develop such a product and that our rings demonstrate dramatic improvement over the current state of the art. The team of investigators is expert in chemistry, pharmacokinetics, engineering, gynecological clinical trials and drug development, and we have experience in all aspects of the drug development process, from concept to approval and marketing. The milestone of this proposal will be the successful completion of this clinical trial demonstrating safety and local delivery of the drug sufficient to merit further clincal trials in pursuit of FDA approval and clinical implementation. The successful completion of this work will be followed by studies and programs to manufacture these rings on a large scale and perform the clinical trials necessary for ultimate approval. As the developers of the only FDA approved sustained release antiviral delivery device we believe we are uniquely qualified to carry out such an ambitious program.