Model-Informed Evaluation of Hydroxyurea Exposure in Special Populations

项目总结/摘要 此K 01应用程序描述了一个为期5年的培训计划，旨在支持董博士获得额外的技能， 知识过渡到一个特殊的研究利基了解药物治疗在怀孕期间， 哺乳期Dong博士是辛辛那提儿童医院临床药理学部的助理教授。 医院医疗中心（CCHMC）。设计的研究将利用她在药代动力学方面的研究专长 (PK)与世界著名的镰状细胞性贫血（SCA）和羟基脲研究中心相结合， CCHMC的药物治疗。SCA是影响全球数百万人的最常见的遗传性疾病之一。 医疗保健的改善使SCA从儿童疾病转变为长期慢性疾病， 生殖健康已成为SCA护理的重要组成部分。羟基脲是一种有效的， 安全的药物治疗，以改善SCA的临床进程。然而，对胎儿毒性的担忧 和新生儿限制了孕妇或哺乳期妇女使用羟基脲。不提供连续 在治疗期间，SCA患者可能会出现严重的并发症，如疼痛危象和中风。 怀孕和产后期间。到目前为止，还没有在这些脆弱人群中进行临床试验。 由于伦理的限制，我们对羟基脲胎盘素的了解仍存在重大知识差距， 在人体内的转移以及在胎儿和母乳喂养的婴儿中的接触。近年来，在计算机生理学上- 基于PBPK的药代动力学（PBPK）模型已经成为预测药物在体内处置的有力工具。 怀孕和产后。本提案的总体目标是评估母亲和母亲的羟基脲暴露情况。 和胎儿/婴儿在怀孕和哺乳期使用全身PBPK模型。该提案代表了 采取创新办法，通过改善孕产妇和婴儿的健康状况， 少数民族的健康状况。本研究包括以下具体目标：1）量化 使用综合PBPK模型评估孕妇和胚胎/胎儿中的羟基脲暴露; 2）评估 采用综合PBPK模型对母乳喂养的新生儿和婴儿的羟基脲暴露进行研究; 3）开发一个 临床决策支持工具，用于预测个体患者的羟基脲暴露。的培养目标 这个K 01奖是为了促进董博士的职业发展，成为一个成功的，独立的，NIH资助的科学家 具有使用计算机模拟PBPK进行母体/胎儿/哺乳期/新生儿全身药物评价的专业知识 方法和决策支持工具的开发。董博士将接受一位杰出的 导师团队由她的主要导师Vinks博士领导，他是定量临床药理学专家， Ware博士是一位非常有成就的血液学家，他领导了许多国际研究工作， 羟基脲处理和SCA护理改善。这个指导团队与均衡的培训相结合， 项目和优秀的研究项目将为董博士的职业发展提供坚实的基础， 研究领域的羟基脲和PBPK建模的特殊人群。

PROJECT SUMMARY/ABSTRACT This K01 application describes a 5-year training plan designed to support Dr. Dong to gain additional skill and knowledge to transition to a special research niche of understanding pharmacotherapy during pregnancy and lactation. Dr. Dong is an Assistant Professor in the Division of Clinical Pharmacology at Cincinnati Children’s Hospital Medical Center (CCHMC). The designed study will leverage her research expertise in pharmacokinetic (PK) modeling coupled with a world renowned research center on sickle cell anemia (SCA) and hydroxyurea pharmacotherapy at CCHMC. SCA is one of the most common genetic disorders affecting millions worldwide. Improvements in medical care have transitioned SCA from a disease of childhood into a long-term chronic illness, and reproductive health has emerged as a significant component in SCA care. Hydroxyurea is an effective and safe pharmacotherapy to ameliorate the clinical course of SCA. However, concerns of toxic effects on fetuses and neonates have limited the use of hydroxyurea in pregnant or lactating women. Without providing continuous management, patients with SCA may develop severe complications such as pain crisis and stroke during pregnancy and postpartum period. So far, no clinical trials could be conducted in these vulnerable populations due to ethical constraints, and significant knowledge gaps remain in our understanding of hydroxyurea placental transfer in humans and its exposure in the fetus and breastfed babies. In recent years, in silico physiologically- based pharmacokinetic (PBPK) modeling has emerged as a powerful tool to predict the drug disposition during pregnancy and postpartum. The overall goal of this proposal is to evaluate hydroxyurea exposure in both mother and fetus/infant during pregnancy and lactation using whole body PBPK modeling. This proposal represents a step forward of using an innovative approach to address health disparities by improving maternal and infant health outcomes in minority populations. The study includes the following Specific Aims: 1) To quantify hydroxyurea exposure in pregnant women and the embryo/fetus using integrated PBPK models; 2) To assess hydroxyurea exposure in breastfeeding newborns and infants with integrated PBPK models; 3) To develop a clinical decision support tool in the prediction of hydroxyurea exposure in individual patients. The training goal of this K01 award is to foster Dr. Dong’s career growth to become a successful, independent, NIH funded scientist who has the expertise in whole body maternal/fetal/lactation/neonatal drug evaluation using an in silico PBPK approach and in decision support tool development. Dr. Dong will receive training from an outstanding mentorship team led by her primary mentor Dr. Vinks, an expert in quantitative clinical pharmacology, and co- mentor Dr. Ware, a highly accomplished hematologist who has led many international research efforts in hydroxyurea treatment and SCA care improvement. This mentoring team in concert with a balanced training program and excellent research project will provide a solid foundation to Dr. Dong’s career development in the field of hydroxyurea research and PBPK modeling for special populations.