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: 8766262
• 负责人: Kevin M Watt
• 金额: $ 12.79万
• 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/8766262
• 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; Clinical Trials Design; 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; 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; public health relevance; research and development; skills; 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）：接受体外膜氧合（ECMO）治疗的儿童是真菌感染的高危人群。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，因此抗真菌药物的适当剂量在这一人群中尚不清楚。瓦特博士将采用一种综合方法来研究在体外膜肺氧合支持下的儿童中最安全和最有效的抗真菌药物剂量。该方法将包括：体外研究评估孤立ECMO电路中的抗真菌处置；复杂的基于生理的药代动力学（PBPK）模型；并通过临床试验对模型进行评价。本提案中开发的PBPK模型通过纳入这些过程的关键生理和物理化学决定因素，扩展了传统的建模技术，从而提供了对药物处置的机制理解，并允许对模型进行修改，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。从这个建议中发展出来的建模技巧将促进