Model-Informed Evaluation of Hydroxyurea Exposure in Special Populations

项目摘要/摘要 此K01应用程序描述了一项为期5年的培训计划，旨在支持董博士获得更多技能和 过渡到了解孕期药物治疗和特殊研究领域的知识 哺乳。董博士是辛辛那提儿童医院临床药理学分部的助理教授 医院医疗中心。这项设计的研究将利用她在药代动力学方面的研究专长。 (PK)建模与世界知名的镰状细胞性贫血(SCA)和羟基尿素研究中心相结合 CCHMC的药物治疗。SCA是影响全球数百万人的最常见的遗传疾病之一。 医疗保健的改善使SCA从一种儿童疾病转变为一种长期的慢性病， 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 安全用药改善SCA的临床病程。然而，对胎儿毒性影响的担忧 新生儿限制了孕妇或哺乳期妇女使用羟基尿素。而不提供连续的 治疗过程中，SCA患者可能会出现严重的并发症，如疼痛危象和中风 孕期和产后期。到目前为止，还不能在这些脆弱的人群中进行临床试验。 由于伦理上的限制，在我们对羟基脲胎盘的理解中仍然存在重大的知识差距 在人类体内的转移及其在胎儿和母乳喂养婴儿中的暴露。近年来，在硅胶生理学方面- 基于药物动力学(PBPK)的药物动力学模型已成为预测药物在体内分布的有力工具 怀孕和产后。这项建议的总体目标是评估两位母亲的羟基尿素暴露情况。 以及孕期和哺乳期的胎儿/婴儿，采用全身PBPK模型。这项提议代表着 采取创新办法，通过改善孕产妇和婴儿的健康状况，解决健康差距问题 少数群体的健康结果。研究包括以下具体目标：1)量化 使用整合的PBPK模型对孕妇和胚胎/胎儿的羟基尿素暴露；2)评估 采用综合PBPK模型的母乳喂养新生儿和婴儿的羟基尿素暴露；3)建立 临床决策支持工具在预测个体患者羟基尿素暴露中的作用。的培训目标 这个K01奖项是为了促进董博士的职业成长，使他成为一名成功的、独立的、由NIH资助的科学家 世卫组织在使用In Silico PBPK进行母体/胎儿/哺乳/新生儿药物评价方面具有专业知识 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，Vinks博士是定量临床药理学方面的专家，并与 导师威尔博士，一位非常有成就的血液学家，领导了许多国际研究工作 羟基脲治疗和SCA护理改善。这支指导团队与均衡的培训协调一致 计划和优秀的研究项目将为董博士在中国的职业发展提供坚实的基础 羟基脲研究领域和针对特殊人群的PBPK建模。

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.