Oseltamivir Use and Risk of Serious Neuropsychiatric Adverse Events in Children

奥司他韦的使用和儿童严重神经精神不良事件的风险

基本信息

批准号：
10427898
负责人：
James W Antoon
金额：
$ 18.46万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427898
关键词：
ABCB1 gene Active Learning Address Adverse drug event Adverse effects Adverse event Algorithms Antiviral Agents Award Biological Blood Brain Caregivers Case Series Child Childhood Chronic Clinical Investigator Clinical Pharmacology Collaborations Consensus Coupled Data Databases Diffuse Diffusion Disease Drug Interactions Drug usage Ensure Evaluation Event Exposure to Family Feeling suicidal Goals High Prevalence Hospitalization Hospitals Incidence Infection Infectious Disease Epidemiology Influenza Kidney Diseases Knowledge Laboratories Leadership Life Literature Medicaid Medical Mental disorders Mentors Methodology Methods Morbidity - disease rate N-Methylaspartate Neurologic Observational Study Oseltamivir Outcome Outpatients Patients Pediatric Hospitals Pediatrics Pharmaceutical Preparations Pharmacoepidemiology Pharmacology Pharmacy facility Population Population Study Proton Pump Provider Psychoses Recording of previous events Reporting Research Research Design Research Infrastructure Research Training Retrospective Studies Retrospective cohort study Risk Safety Schizophrenia Seizures Signal Transduction Suicide Surveys Symptoms System Tennessee Testing Training United States Food and Drug Administration Vital Statistics Work base career career development clinical care clinical practice design experience gamma-Aminobutyric Acid high risk improved influenza infection inhibitor lipophilicity medication safety mortality multidisciplinary neuropsychiatric symptom neuropsychiatry population based programs psychiatric comorbidity randomized trial secondary analysis shared decision making skills socioeconomic disadvantage

项目摘要

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.

项目概要/摘要奥司他韦（达菲）是美国食品和药物管理局 (FDA) 唯一批准的儿童流感药物然而，奥司他韦的处方量不足，包括流感并发症高风险的儿童。关键障碍是父母和提供者对奥司他韦相关潜在不良药物事件的安全性的担忧。医学文献中经常报道奥司他韦，尤其是神经精神不良反应（NPAE）奥司马韦可能通过直接影响 NDMA/GABA 信号传导而引起 NPAE。已知会导致精神分裂症等疾病的神经精神症状。被动地扩散到大脑中，然后通过 P-gp 转运系统快速从大脑中输出。可能导致大脑中高浓度的几种机制，例如通过改变这种 P- 然而，对于奥司他韦与 NPAE 之间的因果关系尚未达成共识。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。迫切需要确定接触奥司他韦的儿童发生 NPAE 的真实风险，以便为临床提供最佳信息实践并澄清患者、其护理人员和提供者的担忧该项目的目的是： 1) 确定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) 检验以下假设同时使用调节 P-gp 的药物可降低奥司他韦相关严重 NPAE 的风险。提出的研究利用了田纳西州医疗补助 (TennCare) 计划的数据，包括生命统计、药物梅西百货索赔数据和医院管理数据每年来自超过 750,000 名儿童，占 50% TennCare 数据库过多地代表了田纳西州的弱势儿童，包括那些患有此类疾病的儿童。该数据库中的儿童数量众多且长期存在。使用这些数据进行成功、高影响力的研究的历史是当前亲的主要优势这些研究的结果将填补有关严重药物不良事件的重要知识空白。儿童并将为流感治疗提供信息。候选人的职业目标是成为独立的人。此外，为了实现这一目标，具有药物流行病学和药物安全性专业知识的临床研究者。为了完成拟议的科学目标，候选人将通过ad- 药物流行病学方法的高级课程、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侧重于观察性研究，以改善儿童在整个奖励过程中，候选人将与多学科导师团队密切合作。和顾问——包括儿科、药物流行病学、临床药理学、传染病专家和流行病学来实现他既定的职业目标和具体目标。