Physiologically Based Pharmacokinetics in Critically Ill Children

描述（由申请方提供）：接受体外膜肺氧合（ECMO）支持的儿童真菌感染风险较高。这些感染通常是致命的，但由于ECMO回路会影响体内的药物水平，因此该人群中抗真菌药物的适当剂量尚不清楚。Watt博士将使用综合方法研究ECMO支持的儿童中最安全和最有效的抗真菌药物剂量。这一办法将包括：评价隔离ECMO回路中抗真菌处置的离体研究;复杂的基于生理学的药代动力学（PBPK）建模;以及通过临床试验进行的模型评价。本提案中开发的PBPK模型通过纳入这些过程的关键生理和理化决定因素来扩展传统建模技术，从而提供对药物处置的机械理解，并允许修改模型以解释系统中的紊乱（例如，肾功能下降，增加ECMO支持）。候选人是一名儿科重症监护医师，致力于以患者为导向的研究，并希望发展复杂的建模技能。从本提案中开发的建模技能将有助于 候选人的长期职业目标是通过将生理学和药理学整合到危重儿童的早期试验的设计和实施中来促进公共卫生。候选人的K23计划的短期职业目标是：1）获得临床药理学，建模和模拟方面的知识和技能; 2）培养成功领导临床试验研究团队的专业技能;和3）产生大量的初步数据和出版物，以支持R 01资助申请，并建立临床药理学独立研究计划。该提案将利用杜克ECMO项目（世界第四大）、杜克临床研究所（DCRI; Benjamin，导师）和Eshelman药学院（Brouwer，共同导师）提供的独特机会。伴随着这项拟议的研究，候选人将通过药物科学博士课程和与导师合作接受药代动力学建模方面的高级培训。组建的导师团队具有独特的资格，优势包括丰富的临床研究经验;在试验设计，研究方法，药理学和建模方面的国际公认的思想领导力;以及初级教师导师的成功历史。在这个计划结束时，瓦特博士将很好地定位为一个独立的医生，科学家领导一个研究小组。

DESCRIPTION (provided by applicant): Children supported with extracorporeal membrane oxygenation (ECMO) are at high risk for fungal infections. These infections are often deadly, but because the ECMO circuit can affect drug levels in the body, the appropriate dosing of antifungal drugs in this population is unknown. Dr. Watt will use an integrative approach to investigate the safest and most effective dose of antifungal drugs in children supported with ECMO. This approach will include: ex vivo studies evaluating antifungal disposition in isolated ECMO circuits; sophisticated physiologically based pharmacokinetic (PBPK) modeling; and model evaluation through clinical trials. The PBPK models developed in this proposal expand on traditional modeling techniques by incorporating the key physiological and physiochemical determinants of these processes, thereby providing a mechanistic understanding of drug disposition and allowing for modification of the model to account for derangements in the system (e.g., decreased renal function, addition of ECMO support). The candidate is a pediatric intensivist with a proven commitment to patient-oriented research, and a desire to develop sophisticated modeling skills. The modeling skills developed from this proposal will facilitate the candidate's long-term career goal to advance public health by integrating physiology and pharmacology into the design and conduct of early-phase trials in critically ill children. The candidate's short-term career goals for the K23 program are to: 1) acquire knowledge and skills in clinical pharmacology, modeling, and simulation; 2) develop the professional skills to successfully lead a 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. This proposal will capitalize on unique opportunities provided by the Duke ECMO program (4th largest in the world), Duke Clinical Research Institute (DCRI; Benjamin, mentor), and the Eshelman School of Pharmacy at UNC (Brouwer, co-mentor). Concomitant with this proposed research, the candidate will receive advanced training in pharmacokinetic modeling through a PhD program in pharmaceutical sciences and through work with his mentors. 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 modeling; and a successful history of mentorship of junior faculty. At the conclusion of this program, Dr. Watt will be well positioned to be an independent physician-scientist leading a research team.