PHARMACOKINETICS OF ANTIMICROBIAL AGENTS IN HIGH RISK INFANTS

描述(由申请人提供)：这份以患者指导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，使布莱恩·史密斯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年龄较大的儿童和成年人获得的数据推断出来的。美罗培南和头孢唑林是两种常用的抗菌药，其PK数据很少。史密斯博士将使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。这一方法将包括：应用清道夫抽样方法、先进的PK-PD模型、将标准护理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。这项建议将利用由NICHD资助的美罗培南儿科非标签研究(Pi Benjamin)提供的独特机会。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；这包括本杰明博士(PI North Carolina Collaborative PPRU)、Capparelli博士(PI University Of San Diego PPRU)和McCracken博士(PI University Texas Southwest PPRU)的参与。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广泛的临床研究经验；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能力；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，并改进临床试验方法，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的正规教学培训相结合，以及来自国家公认的临床试验和儿科药理学专家的指导来发展。相关性(见说明)：尽管一种新生儿药物在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由来已久，但大多数用于婴儿的抗菌药在婴儿中都没有经过充分的研究。这项建议将使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婴儿常用药物的PK，使用以下方法：应用清道夫抽样方法，先进的PK-PD模型，以及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.