Pharmacokinetics and Pharmacodynamics of Antibiotics in Premature Infants

描述（由申请人提供）：这个以患者为导向的指导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根据大龄儿童和成人的数据推断的。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博士将采用综合方法研究这两种药物在早产儿中的药代动力学和药效学。该方法将包括：开发一种多重抗菌测定方法，以测量一个超低容量婴儿血浆样本中五种抗菌药物的药物浓度；稀疏采样方法的应用；高级群体PK/PD模型；并利用临床机会收集样本。该应用程序将利用儿科药理学研究单位资助的试验提供的独特机会，高危婴儿的抗菌PK （PI: Benjamin）。Cohen-Wolkowiez博士还将获得杜克临床研究所和北卡罗来纳大学Eshelman药学院（Kashuba, Pollack）的资源。所组建的导师团队是独一无二的，其优势包括丰富的临床研究经验；在试验设计、研究方法、药理学和PK/PD建模方面具有国际公认的思想领导力；以及指导初级教员的成功经验。Cohen-Wolkowiez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机会，开发一个多重药物分析，掌握PK/PD建模和模拟技术，除了完善临床试验方法，以最大限度地从这个脆弱人群中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公认专家的指导来发展。

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.