Sustained release depot pre-exposure prophylaxis in breast feeding populations

说明(申请人提供)：该项目的长期目标是在资源贫乏的国家防止母婴通过母乳喂养传播艾滋病毒。在发展中国家，通过相对简单的权宜之计，例如在分娩前后给母亲和孩子服用奈韦拉平，可以大大减少围产期传播。然而，在撒哈拉以南非洲，母乳喂养每年仍约占儿童艾滋病病例的315,000例。尽管存在潜在毒性的担忧，但第三阶段试验正在进行中，研究每天给婴儿服用奈韦拉平，以减少这种传播。我们已经开发出一种平台技术，可以通过皮下/肌肉内注射的方式持续释放多种药物，每次注射可能提供6周的保护。纳入这些注射的计划可以利用目前在非洲广泛使用的现有加速DPT免疫方案。在这个项目的第一阶段，我们完成了预定的具体目标：我们研制了奈韦拉平的缓释混悬剂；我们测试了这些制剂在缓冲液中的体外释放特性；我们初步测定了这些制剂在大鼠体内的药代动力学和安全性。这一第二阶段建议的具体目标是：1，优化制剂的生产参数；2，根据FDA的良好制造程序(GMP)为临床试验生产批量；3，根据良好的实验室程序(GLP)，对2种动物进行所需的动物药代动力学和安全性研究；4，向FDA提交试验性新药豁免(IND)申请；该项目的成功完成将迅速导致开发一种注射剂，该剂型能够在断奶期间理想地提供持续的抗病毒血液水平。完成这些目标将是一个容易识别的里程碑，将在第三阶段继续下去，在这一阶段，我们将在志愿者中进行第一阶段测试，并在少数有风险的人群中进行第二阶段测试。最终，一项将日常口服疗法与注射系统进行比较的试验将证明这种方法的潜在价值。撒哈拉以南非洲地区每年有315,000名婴儿通过母乳感染艾滋病毒。缺乏干净的水阻碍了奶瓶的喂养。母亲每天给哺乳婴儿口服奈韦拉平正在进行第三阶段临床试验，但将是资源密集型的。这项工作的目标是开发奈韦拉平的注射药库配方，以减少有效预防计划的基础设施要求，以防止母乳喂养人群中艾滋病毒母婴传播。

DESCRIPTION (provided by applicant): The broad long term goal of this project is to prevent mother to child transmission of HIV through breast feeding in resource poor countries. In the developing world, perinatal transmission is greatly reduced through relatively simple expedients such as dosing mother and child around the time of delivery with nevirapine. However breast feeding still accounts for approximately 315,000 cases annually of pediatric AIDS in sub-Saharan Africa. Despite concerns about potential toxicity, a Phase III trial is underway to study daily oral nevirapine to be given to infants in order to reduce this transmission. We have developed a platform technology for the sustained release of a broad range of drugs by subcutaneous / intramuscular injection that can potentially provide 6 weeks of protection from each injection. A program that incorporates these injections could piggyback onto existing accelerated DPT immunization protocols currently in widespread use in Africa. In Phase 1 of this project we accomplished the specific aims proposed: we formulated sustained release suspensions for nevirapine; we tested the in vitro release characteristics of these formulations into buffer; and we determined preliminary in vivo pharmacokinetics and safety of the formulations in rats. Specific aims of this Phase 2 proposal are to: 1, optimize the production parameters of the formulation; 2, manufacture lots for clinical trials under FDA Good Manufacturing Procedures (GMP); 3, perform required animal pharmacokinetic and safety studies in 2 species under Good Laboratory Procedures (GLP); 4, submit a request for an Investigational New Drug Exemption (IND) to the FDA; The successful completion of this project will lead rapidly to the development of an injectable dosage form that could ideally deliver continuous antiviral blood levels through weaning. Completion of these aims will constitute a readily identifiable milestone that will continue in Phase 3, in which we will carry out Phase 1 testing in volunteers and Phase 2 testing in a small population at risk. Ultimately a trial comparing daily oral therapy to the injectable system will prove the potential value of this approach. Each year 315,000 infants in sub-Saharan Africa are infected by HIV though breast milk. Lack of clean water prevents bottle feeding. Daily oral nevirapine administered by mothers to their breast feeding babies is being tested in a Phase III clinical trial but will be resource intensive. The goal of this work is to develop an injectable drug depot formulation for nevirapine that could reduce the infrastructure requirements for an effective prophylaxis program to prevent mother to child HIV transmission in breast feeding populations.