Sustained release depot pre-exposure prophylaxis in breast feeding populations

描述（由申请人提供）：该项目的广泛长期目标是防止资源匮乏国家通过母乳喂养母婴传播艾滋病毒。在发展中国家，通过相对简单的实验，如在分娩时给母亲和孩子服用奈韦拉平，围产期传播大大减少。然而，在撒哈拉以南非洲，母乳喂养仍然造成每年约315 000例儿童艾滋病病例。尽管对潜在毒性的担忧，III期试验正在进行中，以研究每日口服奈韦拉平给婴儿，以减少这种传播。我们开发了一种平台技术，用于通过皮下/肌内注射持续释放多种药物，每次注射可提供6周的保护。一个包含这些注射的计划可以与目前在非洲广泛使用的现有加速DPT免疫方案相结合。在该项目的第1阶段，我们实现了提出的具体目标：我们配制了奈韦拉平缓释混悬液;我们测试了这些制剂在缓冲液中的体外释放特性;我们初步确定了这些制剂在大鼠中的体内药代动力学和安全性。本II期提案的具体目的是：1，优化制剂的生产参数; 2，根据FDA药品生产质量管理规范（GMP）生产用于临床试验的批次; 3，根据药物非临床研究质量管理规范（GLP）在2个种属中进行所需的动物药代动力学和安全性研究; 4，向FDA提交研究性新药豁免（IND）申请;该项目的成功完成将迅速导致一种注射剂型的开发，该注射剂型可以理想地通过断奶持续提供抗病毒血液水平。这些目标的完成将构成一个易于识别的里程碑，并将在第3阶段继续进行，在第3阶段，我们将在志愿者中进行第1阶段测试，并在少数风险人群中进行第2阶段测试。最终，一项比较每日口服治疗和注射系统的试验将证明这种方法的潜在价值。在撒哈拉以南非洲，每年有315 000名婴儿通过母乳感染艾滋病毒。缺乏干净的水会妨碍奶瓶喂养。母亲对母乳喂养的婴儿每日口服奈韦拉平正在III期临床试验中进行测试，但将是资源密集型的。这项工作的目标是开发一种奈韦拉平的可注射药物贮库制剂，可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的母婴HIV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.