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：
10653016
负责人：
Min Dong
金额：
$ 5.2万
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 2024-01-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653016
关键词：
Address Affect African Age Months American Animal Model Breast Feeding Breastfed infant 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 Techniques Teratogens Time Toxic effect Training Training Programs United States National Institutes of Health Visual Vulnerable Populations Weight Woman appropriate dose breastfed newborn career career development chemical property clinical decision support design dosage dose individualization drug disposition electronic health record system 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

Address Affect African Age Months American Animal Model Breast Feeding Breastfed infant 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 Techniques Teratogens Time Toxic effect Training Training Programs United States National Institutes of Health Visual Vulnerable Populations Weight Woman appropriate dose breastfed newborn career career development chemical property clinical decision support design dosage dose individualization drug disposition electronic health record system 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

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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.

项目摘要/摘要该K01应用程序描述了一项为期5年的培训计划，旨在支持Dong博士，以获得更多的技能和了解过渡到在怀孕期间了解药物治疗的特殊研究的特殊研究。哺乳。 Dong博士是辛辛那提儿童临床药理学系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领域的研究专业知识（PK）建模与世界著名的镰状细胞贫血研究中心（SCA）和羟基脲 CCHMC的药物治疗。 SCA是影响全球数百万的最常见遗传疾病之一。医疗护理的改善已将SCA从童年疾病转变为长期慢性疾病，生殖健康已成为SCA护理中的重要组成部分。羟基脲是一个有效的安全的药物疗法改善SCA的临床过程。但是，对胎儿有毒影响的担忧新生儿限制了羟基脲在孕妇或哺乳期妇女中的使用。不提供连续管理层，SCA患者可能会出现严重的并发症，例如疼痛危机和中风怀孕和产后期。到目前为止，在这些脆弱人群中尚未进行临床试验由于道德的限制，我们对羟基脲占地的理解仍然存在很大的知识差距人类转移及其在胎儿和母乳喂养婴儿中的暴露。近年来，在计算机上基于药代动力学（PBPK）建模已成为预测在怀孕和产后。该提案的总体目标是评估母亲的羟基脲暴露以及使用全身PBPK建模期间怀孕和哺乳期间的胎儿/婴儿。该建议代表通过改善母校和婴儿的创新方法来解决健康分配的发展少数族裔人口的健康成果。该研究包括以下特定目的：1）量化使用集成的PBPK模型，孕妇和胚胎/胎儿暴露羟基脲； 2）评估母乳喂养的新生儿和综合PBPK模型的婴儿中的羟基脲暴露； 3）开发一个临床决策支持工具预测了个别患者的羟基脲暴露。训练目标的该K01奖是要促进Dong博士的职业发展，以成为成功，独立的NIH资助科学家在全身孕产妇/胎儿/哺乳/新生儿药物评估中具有专业知识方法和决策支持工具开发。 Dong博士将获得杰出的培训由她的主要概念Vinks博士领导，Vinks博士是定量临床药理学专家，并共同领导的团队。导师Ware博士是一位出色的血液学家，他领导了许多国际研究工作羟基脲治疗和SCA护理改进。这个心理团队与平衡的训练一起计划和出色的研究项目将为Dong博士的职业发展奠定坚实的基础特殊人群的羟基脲研究和PBPK建模领域。