PHARMACOKINETICS OF ANTIMICROBIAL AGENTS IN HIGH RISK INFANTS

描述（由申请人提供）：这个以指导病人为导向的研究职业计划将提供一个有专家指导的结构化环境，使Brian Smith博士能够发展成为一名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，婴儿的剂量通常是从大龄儿童和成人获得的数据中推断出来的。美罗培南和头孢唑林是两种常用的抗菌剂，其PK数据很少。史密斯博士将采用一种综合的方法来有效地研究这两种药物在婴儿中的PK。这种方法将包括：清除取样方法的应用，先进的PK-PD建模，将标准护理实验室监测整合到试验设计中，并利用临床机会收集样本。该提案将利用nichd资助的试验提供的独特机会，美罗培南儿科标签外研究（PI Benjamin）。史密斯博士还将获得通过儿科药理学研究单位（PPRU）提供的资源；这包括博士的参与。Benjamin (PI北卡罗来纳合作PPRU), Capparelli （PI圣地亚哥大学PPRU）和McCracken （PI德克萨斯大学西南PPRU）。该提案还受益于杜克新生儿围产期研究所（Goldberg）、杜克临床研究所（Benjamin）和北卡罗来纳大学药学院（Thakker）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具有国际公认的思想领导地位；以及指导初级教员的成功经验。Smith博士的长期目标是发展一个临床试验组，专门评估危重婴儿的治疗药物。这个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，以便最大限度地从早产儿有限的样本中获得信息。这些技能将通过药理学和生物静力学方面的正式教学培训以及临床试验和儿科药理学方面的国家认可专家的指导来发展。相关性（见说明书）：尽管新生儿药物在广泛使用之前由于对药物的研究不足而导致灾难性不良事件的历史悠久，但大多数用于婴儿的抗菌素在婴儿中进行的研究不足。本研究将采用一种综合的方法来有效地研究美罗培南和头孢唑林这两种常用的婴儿药物的PK，采用以下方法：应用清除抽样方法，先进的PK- pd建模，并利用临床机会收集样本。

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.