Antimicrobial pharmacokinetics and outcomes in vulnerable infants

描述（由申请人提供）：该候选人是一名新生儿学家，在流行病学方面受过良好的培训，并被证明致力于以患者为导向的研究，并希望发展临床药理学技能。候选人的长期职业目标是通过改善婴儿的药物安全性和剂量来促进公共卫生。候选人在K23项目的短期职业目标是：1)掌握临床药理学的知识和技能；2)培养专业技能，成功领导PK/PD临床试验研究团队；3)提供大量的初步数据和出版物，以支持R01拨款申请，并建立临床药理学的独立研究项目。建议的研究计划，职业发展活动，指导团队和机构环境都是唯一适合帮助申请人实现这些目标。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。氟康唑和利福平是托儿所常用的两种抗微生物药物，其药代动力学数据可以改进。Laughon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。这种方法将包括：稀疏采样方法的应用；群体PK/PD模型；干血斑技术的发展；双中心PK试验；多地点PK试验。该提案将利用氟康唑预防试验（PI: Benjamin，导师）、NICHD PPRU开放标签氟康唑试验和Duke氟康唑试验提供的独特机会。劳顿博士还将获得杜克临床研究所（Benjamin）和北卡罗来纳大学Eshelman药学院（Brouwer，共同导师）的资源。为了支持候选人的职业发展，他将参加北卡罗来纳大学/杜克大学临床药理学奖学金，并获得临床药理学委员会认证。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。Laughon博士的K23提案将为他提供学习PK/PD建模和模拟技术的机会，除了改进临床试验方法外，还将开发干血斑分析，以最大限度地从这一弱势群体的有限样本中获得信息。研究环境包括北卡罗来纳大学的转化和临床科学研究所和杜克大学的DCRI，为追求上述研究和培训目标提供了一个富有成效的、合院的和合作的氛围。在这个项目结束时，劳恩博士将被定位为一名独立的内科科学家，领导一个研究团队。

DESCRIPTION (provided by applicant): The candidate is a neonatologist with strong training in epidemiology and a proven commitment to the study of patient-oriented research, with a desire to develop clinical pharmacology skills. The candidate's long-term career goal is to advance public health by improving drug safety and dosing in infants. The candidate's short- term career goals for the K23 program are to: 1) acquire knowledge and skills in clinical pharmacology; 2) develop the professional skills to successfully lead a PK/PD clinical trial research team; and 3) produce a critical mass of preliminary data and publications to support an R01 grant application and establish a program of independent research in clinical pharmacology. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. 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. Fluconazole and rifampin are two antimicrobials commonly used in the nursery for which pharmacokinetic data can be improved. Dr. Laughon will use an integrative approach to investigate the pharmacokinetics and pharmacodynamics of these two agents in premature infants. This approach will include: application of sparse sampling methodologies; population PK/PD modeling; development of dried blood spot technology; a dual center PK trial; and a multi- site PK trial. This proposal will capitalize on unique opportunities provided by the Fluconazole Prophylaxis trial (PI: Benjamin, mentor), the NICHD PPRU open label fluconazole trial, and the Duke fluconazole trial. Dr. Laughon will also have access to the resources of the Duke Clinical Research Institute (Benjamin) and the Eshelman School of Pharmacy at UNC (Brouwer, co-mentor). To support the candidate's career development, he will participate in the UNC/Duke clinical pharmacology fellowship and become board certified in clinical pharmacology. 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. Laughon's K23 proposal will provide him with the opportunity to learn PK/PD modeling and simulation techniques and to develop a dried blood spot assay in addition to refining clinical trial methodologies to maximize information gained from the limited samples available in this vulnerable population. The research environment including the Translational and Clinical Sciences Institute at UNC and the DCRI at Duke provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. At the conclusion of this program, Dr. Laughon will be positioned to be an independent physician-scientist leading a research team.