PHARMACOKINETICS OF ANTIMICROBIAL AGENTS IN HIGH RISK INFANTS

描述（由申请人提供）：这个指导患者为导向的研究职业建议将提供一个结构化的环境与专家指导，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，婴儿的剂量通常是根据年龄较大的儿童和成人的数据推断的。美罗培南和头孢唑林是两种常用的抗菌药物，其PK数据很少。Smith博士将使用综合方法有效研究这两种药物在婴儿中的PK。这一办法将包括：应用随机抽样方法、先进的PK-PD建模、将标准治疗实验室监测整合到试验设计中，以及利用临床机会收集样本。该提案将利用NICHD资助的试验美罗培南儿科标签外使用研究（PI Benjamin）提供的独特机会。Smith博士还将获得儿科药理学研究单位（PPRU）提供的资源;这包括Benjamin博士（PI北卡罗来纳州协作PPRU）、Capparelli博士（PI圣地亚哥大学PPRU）和麦克拉肯博士（PI德克萨斯大学西南PPRU）的参与。该提案还受益于杜克新生儿围产期研究所（戈德堡）、杜克临床研究所（本杰明）和杜克大学药学院（塔克）的基础设施。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的国际公认的思想领导力;以及初级教师导师的成功历史。史密斯博士的长期目标是建立一个临床试验小组，专门评估危重婴儿的治疗药物。这项K23提案将使他有机会掌握PK/PD建模和模拟技术，并完善临床试验方法，以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，并从国家认可的临床试验和儿科药理学专家的指导下发展。相关性（参见说明）：尽管新生儿药物在其广泛使用之前因药物研究不足而导致灾难性不良事件的历史悠久，但用于婴儿的大多数抗菌药物在婴儿中的研究不足。本提案将采用综合方法，使用以下方法有效研究美罗培南和头孢唑林（两种婴儿常用药物）的PK：应用随机采样方法、先进的PK-PD建模和利用临床机会采集样本。

DESCRIPTION (provided by applicant): 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.