Pharmacokinetics, Pharmacodynamics, and Safety of Methylprednisolone in Neonates on Cardiopulmonary Bypass

摘要 这项以患者为导向的研究职业发展奖将提供一个有专家指导的结构化环境，使 Christoph Hornik 博士能够发展成为危重儿童临床药理学领域的独立研究者和未来领导者。危重疾病会导致严重的生理变化，从而影响药物的处置。如果不考虑这些变化，可能会导致剂量不足、治疗失败或药物毒性。对于接受体外循环心脏手术的危重新生儿来说，这种风险尤其高；药物处置的成熟变化、具有异常解剖结构的复杂基础疾病以及体外循环手术引起的生理变化结合起来显着改变药物处置。尽管其意义重大，但导致这种药物处置改变的潜在机制实际上尚不清楚。鉴于心肺转流术对于危重人群的救生作用，阐明这些机制是一项重要的公共卫生需求。 Hornik 博士建议通过使用一种系统方法来满足这一需求，该方法结合了先进的群体药代动力学/药效学 (PK/PD) 模型、生物标志物和有临床意义的终点。他将使用探针药物甲基泼尼松龙测试拟议的平台，尽管缺乏特定人群的 PK/PD 数据，但该药物仍常规用于体外循环新生儿。他将首先在需要体外循环的心脏手术新生儿中进行甲基泼尼松龙的 PK 试验（目标 1）。该试验将利用儿科试验网络正在进行的多中心机会性 PK 试验的基础设施。接下来，他将使用炎症生物标志物开发甲泼尼龙的群体 PK/PD 模型来表征暴露疗效关系（目标 2）。最后，他将使用开发的 PK/PD 模型来预测药物暴露，并将其与导师之前进行的临床试验中记录的不良事件联系起来（目标 3）。霍尼克博士制定了一项多学科职业发展计划，该计划将利用杜克大学（他在杜克大学担任儿科助理教授）和北卡罗来纳大学教堂山分校（他在该大学攻读制药科学博士学位）的资源。博士课程的结构化和严格的课程与本提案的目标提供的实践培训相结合，将使 Hornik 博士能够发展成为儿科临床药理学研究团队的独立研究员和领导者所需的技能。为了指导他完成这一学术发展，霍尼克博士组建了一支经验丰富的导师团队，他们拥有儿科药理学、机械模型、生物标志物和临床试验方面的专业知识，并且拥有成功指导初级教师的历史。成功完成拟议的以患者为导向的研究职业发展奖后，Hornik 博士将获得必要的先进 PK/PD 建模和临床试验技能，以从事开发用于重症儿童的安全有效药物的终身职业。此外，他还将实现其短期目标，即建立一种系统方法来评估接受体外循环心脏手术的新生儿的药物处置、疗效和安全性。

Abstract This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with expert mentorship to enable Dr. Christoph Hornik to develop as an independent investigator and future leader in the field of clinical pharmacology in critically ill children. Critical illness leads to substantial physiologic alterations which affect drug disposition. Failure to account for these alterations can result in inadequate dosing with therapeutic failures or drug toxicities. This risk is particularly high in critically ill neonates undergoing cardiac surgery requiring cardiopulmonary bypass; maturational changes in drug disposition, complex underlying disease with abnormal anatomy, and physiologic changes induced by the cardiopulmonary bypass procedure combine to significantly alter drug disposition. Despite its significance, the underlying mechanisms responsible for this altered drug disposition are virtually unknown. Given the lifesaving nature of cardiopulmonary bypass in this critically ill population, elucidating these mechanism is an important public health need. Dr. Hornik proposes to respond to this need by using a systematic approach combining advanced population pharmacokinetic/pharmacodynamic (PK/PD) modeling, biomarkers, and clinically meaningful endpoints. He will test the proposed platform using the probe drug methylprednisolone, which is routinely administered to neonates on cardiopulmonary bypass despite lack of population specific PK/PD data. He will first conduct a PK trial of methylprednisolone in neonates undergoing cardiac surgery requiring cardiopulmonary bypass (Aim1).This trial will leverage the infrastructure of an ongoing multicenter opportunistic PK trial conducted by the Pediatric Trials Network. Next, he will develop a population PK/PD model of methylprednisolone using inflammatory biomarkers to characterize the exposure efficacy relationship (Aim 2). Last, he will use the developed PK/PD model to predict drug exposures and associate them with adverse events recorded in clinical trials previously conducted by his mentors (Aim 3). Dr. Hornik developed a multidisciplinary career development plan that will leverage the resources of both Duke University, where he is an assistant professor of pediatrics, and the University of North Carolina at Chapel Hill, where he is enrolled in a PhD program in pharmaceutical sciences. The combination of structured and rigorous coursework of the PhD program with practical training provided by the aims of this proposal, will allow Dr. Hornik to develop the skills necessary to become an independent researcher and leader of a pediatric clinical pharmacology research team. To guide him through this academic development, Dr. Hornik has assembled an experienced mentorship team with expertise in pediatric pharmacology, mechanistic modeling, biomarkers, and clinical trials, and a history of successful mentorship of junior faculty. Upon successful completion of the proposed Mentored Patient-Oriented Research Career Development Award, Dr. Hornik will have acquired the necessary advanced PK/PD modeling and clinical trial skills to pursue a lifelong career developing safe and effective drugs for use in critically ill children. Further, he will have met his short-term goal of establishing a systematic approach to evaluate drug disposition, efficacy, and safety in neonates undergoing cardiac surgery requiring cardiopulmonary bypass.