Ontogeny and Genetics of NSAID Dose-Exposure Relationship in Preterm Infants

早产儿 NSAID 剂量暴露关系的个体发育和遗传学

基本信息

批准号：
10247583
负责人：
Tamorah R Lewis
金额：
$ 12.9万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247583
关键词：
Abdomen Accounting Address Adult Affect Age Algorithms Award Biological Assay Birth Blood Cardiac Surgery procedures Career Choice Child Cities Clinical Clinical Pharmacology Clinical Trials Complex Data Development Doctor of Philosophy Dose Drug Exposure Drug Kinetics Drug Monitoring Drug Targeting Drug resistance Drug toxicity Drug usage Ductus Arteriosus Enzymes Faculty Fellowship Foundations Funding Future Genetic Genetic Variation Genetic study Genotype Gestational Age Goals Grant Growth High Pressure Liquid Chromatography Hospitals In Vitro Individual Indomethacin Infant Intestinal Perforation Investigation Kansas Knowledge Learning Life Liver Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Metabolic Metabolic Biotransformation Metabolic Pathway Metabolism Methodology Methods Missouri Modeling Modification Neonatal Neonatal Intensive Care Units Neonatology Newborn Infant Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Outcome Patent Ductus Arteriosus Pathway interactions Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacology Pharmacometabolomics Physiological Plasma Population Precision therapeutics Pregnancy Premature Infant Prophylactic treatment Regimen Research Research Personnel Sampling Source Techniques Therapeutic Time Tissue Banks Toxic effect Training United States United States National Institutes of Health Universities Urine Variant Vocational Guidance age effect base care outcomes career development clinical care clinical efficacy clinical investigation course development developmental genetics dose individualization drug development drug efficacy drug metabolism drug standard experimental study fetal human tissue improved in vivo individual patient inter-individual variation intraventricular hemorrhage meetings metabolic phenotype metabolomics model building neonate non-genetic patient population pharmacokinetic model physiologically based pharmacokinetics population based postnatal precision drugs predictive modeling preterm newborn professor programs prospective recruit response skills symposium targeted treatment tenure track translational scientist treatment response

项目摘要

Project Summary/Abstract Dr Tamorah Lewis, an Assistant Professor at the University of Missouri Kansas City SOM, is re- applying for a K23 award. After completing fellowships in Neonatology and Clinical Pharmacology (Clin Pharm) and a PhD in Clinical Investigation, she is a tenure-track clinician researcher at Children’s Mercy Hospital. She is awarded a start-up package and 70% protected time and is working to establish herself as a translational investigator in neonatal pharmacology. Her career aspirations include bringing Precision Therapeutics to neonates via the incorporation of pharmacogenetics, pharmacometabolomics and an improved understanding of ontogeny and genetics in variability in drug efficacy and toxicity. The K23 grant will provide: (1) expertise quantifying developmental changes in drug metabolism pathways with in vitro methods (2) learning complex physiologically-based pharmacokinetic (PBPK) modeling techniques to analyze pharmacogenetic and pharmacokinetic results in newborns (3) microsampling methodologies for drug quantification assays and pharmacometabolomic studies, and (4) the skills needed to become an independent NIH-funded investigator. To achieve these goals, (1) J Steven Leeder (Clin Pharm), primary mentor, (2) William Truog (Clinical Trialist), (3) John Jeffrey Reese (Ductus Arteriosus Expert) and (4) Rima Kaddurah-Daouk (Pharmacometabolomics) will serve as the mentorship team. These faculty have a strong track record of mentorship, know Dr Lewis well and have already established collaborative research, and will assist in career development through didactic meetings, frequent formal and informal conferences, and career guidance. The proposed combined approach of in vivo and in vitro experiments addresses an important problem in neonatology and developmental pharmacology, specifically that current indomethacin dosing results in erratic clinical efficacy and toxicity in preterm infants. We propose to study a dose→exposure→response paradigm, focusing on individualizing drug dose to achieve a common target exposure in all infants, thus allowing for the study of variability in drug response at the level of the drug target. Using both in vivo and in vitro data obtained during this K23, we will build an indomethacin dose-exposure model, accounting for gestational age, postnatal age and pharmacogenetics. We hypothesize that developmental variation in metabolic pathways (gestational /postnatal age) and individual genetics will substantially influence indomethacin exposure. The final dose-exposure model will be used prospectively in future drug exposure- response studies. This K23 provides training and enables establishment of a research paradigm for other neonatal drugs where the dose→exposure→response profile is unclear, creating a natural career path for Dr Lewis’ future. The expertise gained and the research results afforded will form the basis for an R01 proposal investigating the variability in indomethacin treatment response given a standard exposure, paving the way for personalized drug use in preterm neonates and improved clinical outcomes.

项目概要/摘要 Tamorah Lewis 博士是密苏里大学堪萨斯城分校 SOM 的助理教授，完成新生儿学和临床药理学（Clin Pharm）奖学金后申请 K23 奖项。她拥有临床研究博士学位，是儿童慈善医院的终身临床医师研究员。获得启动套餐和 70% 的受保护时间，并正在努力将自己打造成转化型人才她是一名新生儿药理学研究员，她的职业抱负包括将精准疗法带入全球。通过结合药物遗传学、药物代谢组学和更好的理解来治疗新生儿 K23 资助将提供：（1）专业知识。用体外方法量化药物代谢途径的发育变化 (2) 学习复合体基于生理学的药代动力学 (PBPK) 建模技术来分析药物遗传学和新生儿药代动力学结果 (3) 用于药物定量测定的微量采样方法和药物代谢组学研究，以及 (4) 成为 NIH 资助的独立研究者所需的技能。为了实现这些目标，(1) J Steven Leeder (Clin Pharm)，主要导师，(2) William Truog (Clinical) 试用者）、(3) John Jeffrey Reese（动脉导管专家）和 (4) Rima Kaddurah-Daouk （药物代谢组学）将作为指导团队，这些教师在以下方面拥有良好的记录。指导，熟悉刘易斯博士并已经建立了合作研究，并将在职业生涯中提供帮助通过说教会议、频繁的正式和非正式会议以及职业指导来实现发展。所提出的体内和体外实验的组合方法解决了一个重要问题在新生儿学和发育药理学中，特别是当前的吲哚美辛剂量会导致早产儿的临床疗效和毒性不稳定，我们建议研究剂量→暴露→反应。范式，侧重于个体化药物剂量，以实现所有婴儿的共同目标暴露，从而允许在体内和体内研究药物靶标水平上药物反应的变异性。根据本次 K23 期间获得的体外数据，我们将建立一个吲哚美辛剂量暴露模型，考虑我们努力解决孕龄、产后年龄和药物遗传学的问题。代谢途径（妊娠/产后年龄）和个体遗传将极大地影响最终剂量暴露模型将前瞻性地用于未来的药物暴露。该 K23 提供培训并为其他研究建立研究范式。剂量→暴露→反应情况尚不清楚的新生儿药物，为博士创造了一条自然的职业道路 Lewis 所获得的专业知识和提供的研究成果将构成 R01 提案的基础。研究标准暴露下吲哚美辛治疗反应的变异性，为早产儿的个性化用药并改善临床结果。