Physiologically Based Pharmacokinetics in Critically Ill Children

危重儿童的基于生理学的药代动力学

• 批准号: 9096855
• 负责人: Kevin M Watt
• 金额: $ 12.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096855
• 关键词: Accounting; Address; Advisory Committees; Affect; Antifungal Agents; Applications Grants; Blood; Candidiasis; Catheters; Cessation of life; Child; Child Support; Childhood; Clinical Pharmacology; Clinical Research; Clinical Trials; Complex; Contracts; Critical Care; Critically ill children; Data; Development Plans; Doctor of Philosophy; Dose; Drug Exposure; Drug Kinetics; Evaluation; Excision; Extracorporeal Membrane Oxygenation; Faculty; Fluconazole; Functional disorder; Funding; Goals; Grant; Health; Infection; Intensive Care Units; Knowledge; Lead; Leadership; Life; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methodology; Micafungin; Modeling; Modification; Morbidity - disease rate; Mycoses; National Institute of Child Health and Human Development; National Institute of General Medical Sciences; Organ; Pediatrics; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacy Schools; Phase; Physicians; Physiological; Physiology; Population; Positioning Attribute; Process; Property; Public Health; Publications; Qualifying; Recording of previous events; Regimen; Renal function; Research; Research Institute; Research Methodology; Resources; Science; Scientist; System; Techniques; Training; Training Programs; Translating; United States; United States National Institutes of Health; Universities; Work; base; career; career development; cohort; design; dosage; drug development; experience; high risk; in vivo; lipophilicity; medical specialties; member; models and simulation; novel; patient oriented research; pediatrician; pharmacokinetic model; post-doctoral training; professor; programs; prospective; research and development; skills; trial design; virtual

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.

描述（由申请人提供）：接受体外膜肺氧合（ECMO）支持的儿童发生真菌感染的风险很高。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 博士将采用综合方法来研究 ECMO 支持儿童中最安全、最有效的抗真菌药物剂量。该方法将包括： 评估隔离 ECMO 回路中抗真菌配置的离体研究；复杂的基于生理学的药代动力学 (PBPK) 模型；并通过临床试验进行模型评估。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，扩展了传统建模技术，从而提供了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，减少肾功能，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，并渴望发展复杂的建模技能。从该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早期试验的设计和实施中来促进公共健康。 K23项目候选人的短期职业目标是：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； 3) 提供大量初步数据和出版物，以支持 R01 拨款申请并建立临床药理学独立研究计划。该提案将利用杜克 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尔曼药学院（Brouwer，联合导师）提供的独特机会。伴随这项拟议的研究，候选人将通过药物科学博士课程以及与导师的合作，接受药代动力学建模方面的高级培训。所组建的导师团队资质独特，优势包括丰富的临床研究经验；在试验设计、研究方法、药理学和建模方面得到国际认可的思想领导力；以及对初级教师进行指导的成功历史。该计划结束后，瓦特博士将成为领导研究团队的独立医师科学家。