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.

NARRATIVE There is no scientific consensus as to whether the antiviral drug, oseltamivir (Tamiflu), the recommended treatment for influenza infection, is associated with neuropsychiatric adverse events (e.g., suicide, psyhocis, seizures etc). This proposal seeks to define the relationship between influenza, oseltamivir, and neuropsychiatric adverse events in children. Results of this research will inform the safety profile of the medication and guide clinical care to optimize outcomes in children with influenza.