PHARMACOKINETICS OF ANTIMICROBIAL AGENTS IN HIGH RISK INFANTS

这个指导病人为导向的研究职业建议将提供一个结构化的环境， 专家指导，这将使布赖恩史密斯博士发展成为一个独立的临床研究人员。 抗生素是住院婴儿最常用的药物;然而， 通常从年龄较大的儿童和成人中获得的数据推断。美罗培南和头孢唑林是两种 几乎没有PK数据可用的常用抗菌剂。史密斯博士将使用一个综合的 有效研究这两种药物在婴儿中的PK的方法。这一办法将包括： 应用随机抽样方法，高级PK-PD建模，整合标准治疗 实验室监测纳入试验设计，并利用临床机会收集样本。这项建议 将利用NICHD资助的试验美罗培南儿科门诊提供的独特机会， 标签研究（PI Benjamin）。史密斯博士还将获得通过儿科提供的资源。 药理学研究单位（PPRU）;包括Benjamin博士（PI北卡罗来纳州）的参与 合作PPRU），卡帕雷利（圣地亚哥PPRU PI大学），和麦克拉肯（得克萨斯州PI大学 西南PPRU）。该提案还受益于杜克新生儿围产期的基础设施 研究所（戈德堡）、杜克临床研究所（本杰明）和药学院 Thakker（Thakker）导师团队的优势包括丰富的临床研究经验; 在试验设计、研究方法和药理学方面具有国际公认的思想领导力;以及 青年教师导师制的成功历史。史密斯博士的长期目标是开展临床试验 专门评估危重婴儿治疗药物的小组。K23的提议将使他能够 有机会掌握PK/PD建模和模拟技术，并完善临床试验方法， 以便最大限度地从早产儿的有限样本中获得信息。这些技能 将通过药理学和生物静力学的正式教学培训相结合， 来自国家认可的临床试验和儿科药理学专家的指导。 相关性（参见说明）： 尽管新生儿医学长期以来由于缺乏足够的研究而导致灾难性的不良事件， 在广泛使用抗生素之前，大多数用于婴儿的抗生素都经历了不充分的 研究婴儿。本提案将采用综合方法有效研究美罗培南的PK 和头孢唑啉，两种常用的婴儿药物，使用以下方法： 采样方法学、先进的PK-PD建模以及利用临床机会收集样本。

This Mentored-Patient Oriented Research Career proposal will provide for a structured environment with expert mentorship that will allow Dr. Brian Smith to develop into an independent clinical researcher. Antibiotics are the most commonly used medications in hospitalized infants; however, dosing for infants is often extrapolated from data obtained in older children and adults. Meropenem and cefazolin are two commonly used antimicrobials for which little PK data are available. Dr. Smith will use an integrative approach to efficiently investigate the PK of these two agents in infants. This approach will include: application of scavenge sampling methodologies, advanced PK-PD modeling, integration of standard of care laboratory monitoring into the trial design, and use of clinical opportunities to collect samples. This proposal will capitalize on the unique opportunities provided by an NICHD-funded trial, Meropenem Pediatric Off- Label Study (PI Benjamin). Dr. Smith will also have access to the resources provided through the Pediatric Pharmacology Research Unit (PPRU); this includes the involvement of Drs. Benjamin (PI North Carolina Collaborative PPRU), Capparelli (PI University of San Diego PPRU), and McCracken (PI University Texas Southwestern PPRU). The proposal also benefits from the infrastructure of the Duke Neonatal Perinatal Research Institute (Goldberg), the Duke Clinical Research Institute (Benjamin) and the School of Pharmacy at UNC (Thakker). The strengths of the mentorship team include extensive clinical research experience; internationally recognized thought leadership in trial design, research methods, and pharmacology; and a successful history of mentorship of junior faculty. Dr. Smith's long term goal is to develop a clinical trial group specializing in evaluating therapeutic agents in critically ill infants. This K23 proposal will allow him the opportunity to master PK/PD modeling and simulation techniques and to refine clinical trial methodologies in order to maximize information gained from the limited samples available in premature infants. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, and from mentorship from nationally recognized experts in clinical trials and pediatric pharmacology. RELEVANCE (See instructions): Despite a neonatal medicine's long history of catastrophic adverse events resulting from inadequate study of drugs prior to their widespread use, the majority of antimicrobials used in infants have undergone insufficient study in infants. This proposal will use an integrative approach to efficiently investigate the PK of meropenem and cefazolin, two agents commonly used in infants, using the following methods: application of scavenge sampling methodologies, advanced PK-PD modeling, and use of clinical opportunities to collect samples.