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

• 批准号: 10576415
• 负责人: James W Antoon
• 金额: $ 18.53万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/10576415
• 关键词: ABCB1 gene; Active Learning; Address; Adverse drug event; Adverse effects; Adverse event; Algorithms; Anti-Arrhythmia Agents; Antibiotics; Antiviral Agents; Award; Biological; Blood; Brain; Caregivers; Case Series; Child; Childhood; Chronic; Clinical Investigator; Clinical Pharmacology; Collaborations; Communicable Diseases; Consensus; Coupled; Data; Databases; Diffusion; Disease; Drug Interactions; Drug Modulation; Drug usage; Ensure; Evaluation; Event; Exposure to; Family; Feeling suicidal; Glucocorticoids; 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 Inhibitors; Provider; Psychoses; Recommendation; 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; Viral; Vital Statistics; Work; 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

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.

项目摘要/摘要 奥司他韦(达菲)是美国食品和药物管理局(FDA)批准的唯一一种儿童流感药物 &lt；12年。然而，奥司他韦的处方不足，包括对流感并发症高危儿童的处方。一 关键障碍是父母和提供者对奥司他韦安全性的担忧。与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(NPAE)，在医学上经常被报道。 在文学和媒体上。Oslemativir可能通过直接作用于NDMA/GABA信号通路而导致NPAE。 大脑，已知在精神分裂症等疾病中会导致神经衰弱症状。奥司他韦 被动地扩散到大脑中，然后通过P-gp运输系统迅速从大脑中输出。那里 可能导致大脑中高浓度的几种机制，例如通过改变这种P- 全科医生运输。然而，关于奥司他韦和NPAE之间的因果关系还没有达成共识。这是 部分由于流感相关神经精神症状的发病背景尚不清楚。 迫切需要确定暴露于奥司他韦的儿童中NPAE的真实风险，以最好地告知临床 实践并澄清患者、他们的照顾者和提供者的顾虑。本项目的目标是：1) 为了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有关的假设；3)检验奥司他韦与严重NPAE有关的假设 同时使用调节P-gp的药物可降低奥司他韦相关的严重NPAE的风险。支持- 提出的研究利用了田纳西州医疗补助(Tennessee Medicaid)计划的数据，包括生命统计数据，Phar- 梅西百货公司的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数据库过度展示了弱势儿童，包括那些患有 慢性病和社会经济劣势。这个数据库中有大量的孩子，而且很长 使用这些数据进行成功的、高影响力的研究的历史是当前PRO- 波萨尔。这些研究的结果将填补关于严重不良药物事件的重要知识空白 并将向儿童提供治疗流感的信息。候选人的职业目标是成为一名独立人士 在药物流行病学和药物安全方面具有专业知识的临床调查员。为了实现这一目标，此外 为了完成拟议的科学目标，候选人将通过以下方式加强其先前的研究培训： 药物流行病学方法方面的高级课程，领导力和指导方面的培训，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 治疗药物安全。在整个奖项过程中，候选人将与一个多学科的导师团队密切合作 和顾问-包括儿科、药物流行病学、临床药理学、传染病方面的专家 和流行病学，以实现他所宣称的职业目标和具体目标。