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

• 批准号: 9792266
• 负责人: Tamorah R Lewis
• 金额: $ 15.79万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792266
• 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; intraventricular hemorrhage; meetings; metabolic phenotype; metabolomics; model building; neonate; non-genetic; patient population; pharmacokinetic model; physiologically based pharmacokinetics; population based; postnatal; predictive modeling; professor; programs; prospective; recruit; response; skills; symposium; targeted treatment; tenure track; translational scientist; treatment response

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.

项目总结/摘要 塔莫拉刘易斯博士，助理教授在密苏里州堪萨斯城SOM的大学，是重新- 申请K23奖在完成新生儿学和临床药理学（临床药学）的研究金后 和临床研究博士学位，她是儿童慈善医院的终身临床研究员。她 被授予启动包和70%的保护时间，并正在努力建立自己的翻译 新生儿药理学研究员。她的职业抱负包括将Precision Therapeutics带到 新生儿通过药物遗传学，药物代谢组学和提高认识的结合 个体发育和遗传学在药物功效和毒性的变异性中的作用。K23赠款将提供：（1）专业知识 用体外方法定量药物代谢途径的发育变化（2）学习复合物 基于生理学的药代动力学（PBPK）建模技术，以分析药物遗传学和 新生儿中的药代动力学结果（3）用于药物定量测定的微量取样方法， 药物代谢组学研究，以及（4）成为独立NIH资助的研究者所需的技能。 为了实现这些目标，（1）J Steven利德（临床制药），主要导师，（2）William Truog（临床 Trialist），（3）John Jeffrey Reese（Dendritic Arteriosus专家）和（4）Rima Kaddurah-Daouk （药物代谢组学）将担任导师团队。这些教师有一个强大的跟踪记录， 导师，了解博士刘易斯以及已经建立了合作研究，并将协助职业生涯 通过教学会议、经常的正式和非正式会议以及职业指导来促进发展。 所提出的体内和体外实验相结合的方法解决了一个重要的问题 在发育学和发育药理学中，特别是目前吲哚美辛给药导致 早产儿临床疗效和毒性不稳定。我们建议研究剂量→暴露→反应 范例，侧重于个体化药物剂量，以实现所有婴儿的共同目标暴露，因此 允许在药物靶水平上研究药物反应的可变性。使用体内和体内 在此K23期间获得的体外数据，我们将建立吲哚美辛剂量暴露模型，解释 胎龄、出生后年龄和药物遗传学。我们假设， 代谢途径（妊娠/出生后年龄）和个体遗传学将显著影响 吲哚美辛暴露。最终剂量-暴露模型将前瞻性地用于未来的药物暴露- 响应研究。这K23提供培训，并使建立一个研究范式，为其他 新生儿药物的剂量→暴露→反应曲线尚不清楚，为Dr 刘易斯的未来。获得的专业知识和提供的研究结果将构成R 01提案的基础 研究标准暴露下吲哚美辛治疗反应的变异性，为以下研究铺平道路： 早产儿的个性化药物使用和改善的临床结果。