Physiologically Based Pharmacokinetics in Critically Ill Children

描述(由申请人提供)：接受体外膜氧合(ECMO)支持的儿童有很高的真菌感染风险。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，因此这一人群中抗真菌药物的适当剂量尚不清楚。瓦特博士将使用一种综合的方法来研究在ECMO支持下的儿童中最安全和最有效的抗真菌药物剂量。这一方法将包括：评估隔离ECMO回路中抗真菌处置的体外研究；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模型评估。本提案中开发的PBPK模型扩展了传统建模技术，纳入了这些过程的关键生理和物理化学决定因素，从而提供了对药物处置的机械理解，并允许修改模型以考虑系统中的紊乱(例如，肾功能下降，增加ECMO支持)。应聘者是一名儿科强化师，致力于以患者为中心的研究，并渴望发展复杂的建模技能。从这份提案中发展出来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早期试验的设计和实施中来促进公共健康。候选人对K23项目的短期职业目标是：1)获得临床药理学、建模和模拟方面的知识和技能；2)发展成功领导临床试验研究团队的专业技能；3)产生大量的初步数据和出版物，以支持R01拨款申请，并建立临床药理学独立研究计划。这项建议将利用杜克ECMO项目(世界第四大)、杜克临床研究所(DCRI；本杰明，导师)和北卡罗来纳大学埃谢曼药学院(布鲁沃，共同导师)提供的独特机会。伴随着这项拟议的研究，候选人将通过药学博士项目和与他的导师的合作，接受药物动力学建模方面的高级培训。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、药理学和建模方面的国际公认的思想领导；以及初级教师的成功导师历史。在这个项目结束时，瓦特博士将成为一名独立的内科科学家，领导一个研究团队。

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.