Oseltamivir Use and Risk of Serious Neuropsychiatric Adverse Events in Children

项目总结/摘要 奥司他韦（达菲）是唯一的食品和药物管理局（FDA）批准的儿童流感药物 < 12年。然而，奥司他韦的处方量不足，包括在流感并发症高危儿童中。一 主要障碍是父母和提供者对奥司他韦安全性的担忧。潜在药物不良事件相关 奥司他韦，特别是神经精神不良反应（NPAEs），经常在医学文献中报道- 自然和媒体。Oslemativir可能通过直接影响NDMA/GABA信号传导引起NPAE， 大脑，这是众所周知的，导致神经精神分裂症等疾病的症状。Oseltamivir 被动扩散到脑中，然后通过P-gp转运系统迅速输出到脑外。那里 几种可能导致大脑中高浓度的机制，例如通过改变这种P- gp运输。然而，关于奥司他韦和非质子酸酯之间的因果关系尚未达成共识。这是 部分原因是流感相关神经精神症状的背景发病率尚不清楚。 迫切需要确定暴露于奥司他韦的儿童发生NPAE的真实风险，以最好地告知临床 实践并澄清患者、其护理人员和提供者的担忧。该项目的目标是：1） 定义儿童中流感相关严重神经精神症状的人群发病率， 2)检验奥司他韦与严重NPAE相关的假设，以及3）检验 同时使用调节P-gp的药物可改变奥司他韦相关严重NPAE的风险。亲- 提出的研究利用田纳西州医疗补助计划（TennCare）的数据，包括重要统计数据，phar， 梅西索赔数据和医院管理数据，每年超过75万名儿童，占50%， 田纳西州的孩子们TennCare数据库过度呈现了弱势儿童，包括那些 慢性病和社会经济劣势。这个数据库中的大量儿童， 使用这些数据进行的成功，高影响力研究的历史是当前亲的主要优势， 提议。这些研究的结果将填补关于严重药物不良事件的重要知识空白， 儿童，并将告知治疗流感。候选人的职业目标是以独立人士的身份出现 具有药物流行病学和药物安全性专业知识的临床研究者。为了实现这一目标，此外， 为了完成拟议的科学目标，候选人将增加他以前的研究训练， 药物流行病学方法高级课程，领导力和指导培训，以及实践经验， FDA和儿童医院协会的经验集中在观察性研究，以改善儿科， 药物安全。在整个过程中，候选人将与多学科的导师团队密切合作 包括儿科、药物流行病学、临床药理学、传染病 和流行病学，以实现他的职业目标和具体目标。

PROJECT SUMMARY/ABSTRACT Oseltamivir (Tamiflu) is the only Food and Drug Administration (FDA) approved influenza medication for children < 12 years. Yet, oseltamivir is under prescribed, including in children at high risk for influenza complications. One key barrier is parental and provider concern about the safety of oseltamivir. Potential adverse drug events related to oseltamivir, especially neuropsychiatric adverse effects (NPAEs), are frequently reported in the medical liter- ature and in the media. Oslemativir may cause NPAEs through direct effects on NDMA/GABA signaling in the brain, which is known to cause neurospcyahitric symptoms in diseases such as schizophrenia. Oseltamivir passively diffuses into the brain and is then rapidly exported out of the brain by the P-gp transport system. There several mechanisms that might result in high concentrations in the brain, such as through alterations in this P- gp transport. However, there is no consensus on a causal relationship between oseltamivir and NPAEs. This is in part because of the background incidence of influenza associated neuropsychiatric symptoms is not known. There is a critical need to define the true risk of NPAE in children exposed to oseltamivir to best inform clinical practice and clarify the concerns of patients, their caregivers, and providers. The aims of this project are to: 1) to define the population-based incidence of influenza associated serious neuropsychiatric symptoms in children, 2) to test the hypothesis that oseltamivir is associated with serious NPAE and 3) to test the hypothesis that concurrent use of drugs modulating P-gp modifies the risk of oseltamivir associated serious NPAE. The pro- posed studies leverage data from the Tennessee Medicaid (TennCare) program comprising vital statistics, phar- macy claims data, and hospital administrative data from more than 750,000 children per year, representing 50% of Tennessee’s children. The TennCare database overrespresents vulnerable children, including those with chronic conditions and socioeconomic disadvantages. The large number of children in this database, and long history of successful, high-impact research conducted using these data are major strengths of the current pro- posal. The results of these studies will fill an important knowledge gap regarding serious adverse drug events in children and will inform treatment for influenza. The candidate’s career goal is to emerge as an independent clinical investigator with expertise in pharmacoepidemiology and drug safety. To accomplish this goal, in addition to completion of the proposed scientific aims, the candidate will augment his prior research training with ad- vanced coursework in pharmacoepidemiology methods, training in leadership and mentoring, and practical ex- periences with the FDA and Children's Hospital Association focused on observational studies to improve pedi- atric drug safety. Throughout this award, the candidate will work closely with a multidisciplinary team of mentors and advisors-including experts in pediatrics, pharmacoepidemiology, clinical pharmacology, infectious disease and epidemiology to carry out his stated career objectives and specific aims.