A Model Based Approach to Individualizing Antimicrobial Dosing in Pediatric Sepsis

项目总结/摘要 脓毒症是儿科重症监护病房死亡的主要原因。给药的处置 在脓毒症期间，受脓毒症相关的病理生理学变化的影响。然而，如何准确的影响 这些变化影响抗菌药物的药代动力学（PK），而抗菌药物是治疗的主要手段，目前尚不清楚。这 如果不进行剂量调整，知识差距使这一人群面临治疗失败的重大风险 以适应这些PK差异。这项研究将集中在量化的病理生理变化 败血症，改变处置肾脏清除抗菌药物，使用头孢吡肟作为候选药物。 该提案的总体目标是通过量化脓毒症相关的 影响头孢吡肟分布的病理生理学变化和个体受试者协变量， 纳入基于模型的给药策略，以达到目标浓度。拟议 K99期间的研究将收集头孢吡肟PK样本并量化脓毒症相关的生理变化 使用多普勒成像和身体评估来评估肾功能。这些数据将被分析， 群体非线性混合效应模型在K99中的拟议研究将为我提供经验 临床试验设计，实施和分析以及对伦理考虑的理解 儿科临床研究这些都是我还没有机会学习的技能，对我来说是必不可少的。 成为独立的儿科临床药理学家 R 00期间的拟议研究将调整并纳入K99的结果，以制定 基于生理学的PK模型。然后将在前瞻性临床试验中对该模型进行评价。 试验使用来自模型模拟的给药方案，每例患者的剂量将个体化 使用贝叶斯分析来评估床旁个体化剂量的可行性。此外，结果 还将纳入本试验的数据，以更新整个人口的模型。的结果 该提案将有助于建立一个“虚拟危重儿童”模型，可用于肾清除抗菌药物。 在临床中应用该模型将个性化给药，以提高脓毒症儿童的安全性和有效性。 费城儿童医院的环境和基础设施支持整合研究 临床护理，使其成为拟议研究的理想地点。本次资助的指导团队 由重症监护、儿科药理学和药物计量学领域的专家组成。职业 发展计划包括在先进的药物计量学，人类受试者保护， 研究伦理学、临床研究开发和儿科重症监护药理学， 研究和教学。这一培训计划和指导将有助于建立基础， 作为一个独立的研究人员成功的职业生涯，并帮助我过渡到终身教职。

PROJECT SUMMARY/ABSTRACT Sepsis is the leading cause of deaths in pediatric intensive care units. The disposition of drugs administered during sepsis are impacted by sepsis-associated pathophysiological changes. However, the exact impact of how these changes influence the pharmacokinetics (PK) of antimicrobials, the mainstay of therapy, is unknown. This knowledge gap places this population at a substantial risk for treatment failures if dose adjustments are not made to accommodate these PK differences. This research will focus on quantifying the pathophysiological changes of sepsis that alter the disposition of renally cleared antimicrobials, using cefepime as a candidate drug. The overall goal of this proposal is to individualize cefepime dosing by quantifying sepsis-associated pathophysiological changes and individual subject covariates that impact cefepime disposition, which will then be incorporated into a model-based dosing strategy for the attainment of target concentrations. The proposed studies during the K99 will collect cefepime PK samples and quantify sepsis-associated physiological changes in renal function using Doppler imaging and physical assessments. This data will then be analyzed using population nonlinear mixed effects modeling. The proposed research in the K99 will provide me with experience in clinical trial design, implementation, and analysis as well as an understanding of the ethical considerations of pediatric clinical research. These are skills that I have not yet had an opportunity to learn, and are essential to becoming an independent pediatric clinical pharmacologist. The proposed studies during the R00 will adapt and incorporate the results of the K99 in order to develop a physiologically based PK model for pediatric sepsis. The model will then be evaluated in a prospective clinical trial using a dosing regimen derived from model simulations and the dose will be individualized for each patient using a Bayesian analysis to assess the feasibility of personalizing doses at the bedside. Additionally, results from this trial will also be incorporated to update the model for the population as a whole. The results of this proposal will help establish a “virtual critically ill child” model which can be used for renally cleared antimicrobials. Applying this model in the clinic will personalize dosing to improve safety and efficacy in children with sepsis. The environment and infrastructure at The Children's Hospital of Philadelphia supports integrating research into clinical care, making it the ideal location for the proposed research. The mentoring team for this grant has been formed with experts in the fields of critical care, pediatric pharmacology, and pharmacometrics. The career development plan includes extensive training in advanced pharmacometrics, human subjects protection, research ethics, clinical research development, and pediatric critical care pharmacology through hands-on research and didactics. This training plan and mentorship will help build the foundations that will lead to a successful career as an independent researcher and help me transition to a tenure-track faculty position.