Pharmacokinetics and Pharmacodynamics of Antibiotics in Premature Infants

描述(由申请者提供)：这一以患者为导向的有指导的研究职业发展申请将提供一个有专家指导的结构化环境，使Michael Cohen-Wolkowiez博士能够发展成为一名独立的临床研究人员。虽然抗生素是住院婴儿最常用的药物，但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。哌拉西林/他唑巴坦和甲硝唑是托儿所常用的两种抗菌剂，其在早产儿中的药代动力学数据很少。Cohen-Wolkowiez博士将使用一种综合方法来研究这两种药物在早产儿中的药代动力学和药效学。这一方法将包括：开发一种多重抗菌素分析，以测量一个超低容量婴儿血浆样本中五种抗菌剂的药物浓度；应用稀疏抽样方法；先进的人口PK/PD模型；以及利用临床机会收集样本。这一应用将利用儿科药理学研究单位资助的试验--高危婴儿中的抗菌素PK(PI：Benjamin)--提供的独特机会。科恩-沃尔科维兹博士还将获得杜克临床研究所和北卡罗来纳大学埃谢曼药学院(波拉克卡舒巴)的资源。组建的导师团队是唯一合格的，优势包括广泛的临床研究经验；在试验设计、研究方法、药理学和PK/PD模型方面的国际公认的思想领导；以及初级教师导师的成功历史。科恩-沃尔科维兹博士的长期目标是通过改善婴儿抗生素的安全性和剂量来促进公众健康。这个K23应用程序将为他提供开发多重药物分析的机会，并掌握PK/PD建模和模拟技术，此外还可以改进临床试验方法，以最大限度地从这一脆弱人群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规教学培训相结合，以及通过国家公认的临床试验和儿科药理学专家的指导来发展。 公共卫生相关性：相关性陈述早产儿侵袭性感染很常见，而且往往是致命的。因此，医生通常会开出抗菌剂来治疗这一人群中的疑似或确诊感染。大多数抗菌药在婴儿中的适当剂量尚不清楚，从老年患者那里获得的信息往往无法准确预测新生儿的药物处置情况。这项应用将使用一种新的方法来研究婴儿常用的抗菌剂的药代动力学和药效学，使用超低容量多重分析、清除采样方法和先进的PK-PD建模。

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development application will provide for a structured environment with expert mentorship that will enable Dr. Michael Cohen-Wolkowiez to develop as an independent clinical researcher. Although antibiotics are the most commonly used medications in hospitalized infants, dosing for infants is often extrapolated from data obtained in older children and adults. Piperacillin/tazobactam and metronidazole are two antimicrobials commonly used in the nursery for which few pharmacokinetic data are available in premature infants. Dr. Cohen-Wolkowiez will use an integrative approach to investigate the pharmacokinetics and pharmacodynamics of these two agents in premature infants. This approach will include: development of a multiplex antimicrobial assay to measure drug concentrations of five antimicrobials in one ultra-low-volume infant plasma sample; application of sparse sampling methodologies; advanced population PK/PD modeling; and use of clinical opportunities to collect samples. This application will capitalize on unique opportunities provided by the Pediatric Pharmacology Research Unit-funded trial, Antimicrobial PK in High-Risk Infants (PI: Benjamin). Dr. Cohen-Wolkowiez will also have access to the resources of the Duke Clinical Research Institute and the Eshelman School of Pharmacy at UNC (Kashuba, Pollack). The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience; internationally recognized thought leadership in trial design, research methods, pharmacology, and PK/PD modeling; and a successful history of mentorship of junior faculty. Dr. Cohen-Wolkowiez's long-term goal is to advance public health by improving antibiotic safety and dosing in infants. This K23 application will provide him with the opportunity to develop a multiplex drug assay and to master PK/PD modeling and simulation techniques in addition to refining clinical trial methodologies to maximize information gained from the limited samples available in this vulnerable population. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, as well as through mentoring from nationally recognized experts in clinical trials and pediatric pharmacology. PUBLIC HEALTH RELEVANCE: Relevance Statement Invasive infections in premature infants are common and often fatal. Therefore, physicians commonly prescribe antimicrobial agents to treat suspected or confirmed infections in this population. Appropriate dosing of most antimicrobial agents in infants is unknown and information obtained from older patients often has failed to accurately predict newborn drug disposition. This application will use a novel approach to investigate the pharmacokinetics and pharmacodynamics of antimicrobial agents commonly used in infants, using an ultra-low volume multiplex assay, scavenge sampling methodologies, and advanced PK-PD modeling.