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

甲基泼尼松龙在体外循环新生儿中的药代动力学、药效学和安全性

• 批准号: 9222890
• 负责人: Christoph Hornik
• 金额: $ 16.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222890
• 关键词: Adult; Adverse event; Affect; Anatomy; Biological Markers; Biometry; Cardiac Surgery procedures; Cardiology; Cardiopulmonary Bypass; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Complex; Control Groups; Critical Care; Critical Illness; Critically ill children; Data; Development; Development Plans; Disease; Doctor of Philosophy; Dose; Drug Exposure; Drug Kinetics; Drug toxicity; Drug usage; Enrollment; Environment; Faculty; Failure; Fluid overload; Funding; Future; Glucose; Goals; Grant; Hour; Inflammation; Inflammatory; Institution; Interleukin-10; Interleukin-6; International; K-Series Research Career Programs; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methylprednisolone; Modeling; National Institute of Child Health and Human Development; Nature; Neonatal; North Carolina; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Pharmacy Schools; Phase; Physiological; Physiology; Placebo Control; Population; Procedures; Property; Public Health; Recording of previous events; Research; Research Infrastructure; Research Institute; Research Personnel; Resources; Risk; Safety; Sampling; Science; Secure; Serum; Statistical Data Interpretation; Structure; Supervision; Techniques; Testing; Therapeutic; Toxic effect; Training; United States National Institutes of Health; Universities; Writing; career; career development; congenital heart disorder; drug efficacy; experience; mid-career faculty; model development; multidisciplinary; natural hypothermia; neonate; pediatric pharmacology; pharmacodynamic model; professor; programs; randomized trial; response; skills; therapy outcome; trial design; virtual

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.

摘要 这个指导以患者为导向的研究职业发展奖将提供一个结构化的环境与专家指导，使克里斯托弗·霍尼克博士发展成为一个独立的研究者和未来的领导者在重症儿童的临床药理学领域。危重病导致影响药物处置的实质性生理改变。未能解释这些变化可能导致治疗失败或药物毒性的剂量不足。在接受需要体外循环的心脏手术的危重新生儿中，该风险尤其高;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由体外循环程序联合收割机诱导的生理变化联合起来显著改变药物处置。尽管其意义重大，但这种改变药物处置的潜在机制实际上是未知的。鉴于心肺转流术在这一危重人群中的救命性质，阐明这些机制是一个重要的公共卫生需求。Hornik博士建议通过使用一种系统性方法，结合先进的群体药代动力学/药效学（PK/PD）建模、生物标志物和有临床意义的终点来应对这一需求。他将使用探针药物甲泼尼龙测试拟定平台，尽管缺乏人群特异性PK/PD数据，但甲泼尼龙常规用于体外循环新生儿。他将首先在接受需要心肺转流的心脏手术的新生儿中进行甲基强的松龙的PK试验（Aim 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基强的松龙的群体PK/PD模型，以表征暴露疗效关系（目的2）。最后，他将使用开发的PK/PD模型来预测药物暴露，并将其与之前由他的导师进行的临床试验中记录的不良事件相关联（目标3）。Hornik博士制定了一个多学科的职业发展计划，该计划将利用杜克大学的资源，他在那里担任儿科助理教授，以及查佩尔山的北卡罗来纳州大学，他在那里攻读制药科学博士学位。博士课程的结构化和严格的课程与本提案的目的所提供的实践培训相结合，将使Hornik博士能够发展成为独立研究人员和儿科临床药理学研究团队领导者所需的技能。为了指导他完成这一学术发展，Hornik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，机械建模，生物标志物和临床试验方面的专业知识，以及初级教师成功导师的历史。在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，以追求终身职业，开发用于重症儿童的安全有效的药物。此外，他将达到他的短期目标，建立一个系统的方法来评价药物处置，疗效和安全性的新生儿接受心脏手术，需要心肺转流。