Model-Informed Evaluation of Hydroxyurea Exposure in Special Populations

特殊人群羟基脲暴露的模型知情评估

基本信息

批准号：
10427738
负责人：
Min Dong
金额：
$ 12.7万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-24 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427738
关键词：
Address Affect African Age-Months American Animal Model Breast Feeding Caring Cessation of life Child Childhood Chronic Disease Clinical Clinical Pharmacology Clinical Trials Congenital Abnormality Coupled Data Development Disease Dose Drug Evaluation Drug Exposure Drug Kinetics Electronic Health Record Embryo Ethics Evaluation Exposure to Fetal Hemoglobin Fetus First Pregnancy Trimester Fostering Foundations Funding Future Genetic Diseases Goals Growth Hematologist Human Human Milk Infant Infant Health Interdisciplinary Study International Knowledge Laboratories Lactation Literature Maternal Health Medical Medical center Medicine Mentored Research Scientist Development Award Mentors Mentorship Minority Groups Modeling Mothers Neonatal Newborn Infant Organ Outcome Pain Patients Pediatric Hospitals Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Physiology Population Positioning Attribute Postpartum Period Pregnancy Pregnant Women Recommendation Renal function Reproductive Health Research Research Design Research Personnel Research Project Grants Research Proposals Risk Safety Scientist Sickle Cell Sickle Cell Anemia Solid Special Population Stroke System Techniques Teratogens Time Toxic effect Training Training Programs United States National Institutes of Health Visual Vulnerable Populations Weight Woman appropriate dose base breastfed newborn career career development chemical property clinical decision support design dosage dose individualization drug disposition embryo/fetus experience fetal health disparity hydroxyurea improved in silico individual patient innovation interest malformation maternal morbidity mortality neonatal exposure neonate patient health information perinatal morbidity pharmacokinetic model placental transfer pregnant premature prenatal exposure prevent professor research study skills support tools teratogenesis tool tool development

项目摘要

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.

项目概要/摘要此 K01 申请描述了一项为期 5 年的培训计划，旨在支持董博士获得额外的技能和过渡到了解怀孕期间药物治疗的特殊研究领域的知识董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业知识。 (PK) 建模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 的药物治疗是影响全球数百万人的最常见遗传性疾病之一。医疗保健的进步使 SCA 从一种儿童疾病转变为一种长期慢性疾病，生殖健康已成为 SCA 护理的重要组成部分，羟基脲是一种有效且有效的药物。安全的药物治疗可改善 SCA 的临床病程，但对胎儿的毒性作用令人担忧。和新生儿限制了孕妇或哺乳期妇女使用羟基脲，而不提供连续的治疗。管理方面，SCA 患者在治疗过程中可能会出现严重的并发症，例如疼痛危象和中风。到目前为止，还无法在这些易感人群中进行临床试验。由于伦理限制，我们对羟基脲胎盘素的理解仍然存在重大知识差距近年来，在计算机生理学上，人类的传播及其在胎儿和母乳喂养的婴儿中的暴露。基于药代动力学 (PBPK) 的模型已成为预测药物在治疗过程中的药物分布的强大工具。该提案的总体目标是评估母亲和母亲的羟基脲暴露情况。怀孕和哺乳期间的胎儿/婴儿使用全身 PBPK 模型。进一步采用创新方法，通过改善孕产妇和婴儿的健康状况来解决健康差距该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/胎儿的羟基脲暴露；母乳喂养新生儿和婴儿的羟基脲暴露综合 PBPK 模型；预测个体患者羟基脲暴露的临床决策支持工具的培训目标。 K01 奖旨在促进董博士的职业发展，使其成为一名成功的、独立的、由 NIH 资助的科学家拥有使用计算机 PBPK 进行全身母体/胎儿/哺乳期/新生儿药物评估的专业知识董博士将接受杰出人士的培训。由她的主要导师 Vinks 博士（定量临床药理学专家）领导的导师团队，以及导师 Ware 博士是一位卓有成就的血液学家，在以下领域领导了许多国际研究工作羟基脲治疗和SCA护理改进这指导团队配合进行了均衡的培训。项目和优秀的研究项目将为董博士在该领域的职业发展提供坚实的基础羟基脲研究和特殊人群的 PBPK 建模领域。