Drug-Drug Interactions and Preventable Adverse Events in Rheumatology

描述（由申请人提供）：肌肉骨骼疾病是美国致残的主要原因，占50岁以上人群所有慢性病的一半以上。许多用于治疗肌肉骨骼疾病的药物都有可预防的危及生命的副作用。减少此类严重不良事件的干预措施的一个重要目标是药物-药物相互作用。特别重要的是由CYP3A介导的药物相互作用，CYP3A是细胞色素P-450 （CYP）成员，参与超过60%的药物代谢。该提案将定义CYP3A介导的药物-药物相互作用的风险及其作为解释通常用于治疗肌肉骨骼疾病患者的药物可预防不良事件的潜在机制的作用。使用最先进的药物流行病学技术和TennCare和Medicare入选者的大型数据库，这些研究将聚集接受具有巨大潜在毒性的CYP3A底物药物的队列：(1)阿片类药物羟考酮和芬太尼，(2)秋水仙碱使用者，并确定与CYP3A抑制剂同时治疗相关的临床重要结局的风险。更好地了解这些风险将引导从业者避免同时使用导致临床显著毒性的相互作用药物。申请人钟博士在临床和流行病学研究方面有很强的背景，并致力于风湿病学和药物流行病学的学术生涯。她获得了范德比尔特大学公共卫生硕士学位，并完成了临床药理学的额外培训，由T-32资助。同时，她完成了美国内科医学研究委员会风湿病学研究。钟博士的职业目标是成为一名独立的研究者，该计划旨在加强她在药物流行病学，高级生物统计学和临床药理学方面的知识。这些都是她在R01基金中具有竞争力的必要技能。范德比尔特大学为她提供了一个特殊的环境来发展成功的独立事业。医学系、风湿病学和药物流行病学部门的领导完全支持她的计划。此外，钟博士的导师。Ray和Stein，是国际公认的，在指导独立调查员方面有着成功的记录，资金充足，并且投入了必要的时间和资源来培训她并促进她的职业发展。K-23奖项将使钟博士能够发挥自己的优势，并获得受保护的时间和资源，以获得在风湿病学和药物流行病学学术领域独立职业所需的技能。

DESCRIPTION (provided by applicant): Musculoskeletal disorders are the leading cause of disability in the U.S. and account for more than half of all chronic conditions in people older tha 50 years. Many drugs used to treat musculoskeletal conditions have preventable life threatening side effects. An important target for interventions to decrease such severe adverse events is drug-drug interactions. Particularly important are drug interactions mediated by CYP3A, the cytochrome P-450 (CYP) member that is involved in the metabolism of more than 60% of all drugs. This proposal will define the risk of CYP3A mediated drug-drug interactions and their role as underlying mechanisms explaining preventable adverse events for drugs commonly used to treat patients with musculoskeletal conditions. Using state of the art pharmacoepidemiologic techniques and large databases of TennCare and Medicare enrollees, the studies will assemble cohorts receiving selected CYP3A substrate drugs with great potential for toxicity: (1) the opioids oxycodone and fentanyl and (2) colchicine users and define the risk of clinically important outcomes associated with concurrent therapy with CYP3A inhibitors. Better understanding of these risks will lead practitioners to avoid concomitant use of interacting drugs that lead to clinically significant toxicity. The applicant, Dr. Chung, has a strong background in clinical and epidemiological research and is committed to an academic career in rheumatology and pharmacoepidemiology. She obtained a Master of Public Health degree at Vanderbilt and completed additional training in clinical pharmacology, funded by a T-32 grant. Concurrently, she completed rheumatology fellowship under the American Board of Internal Medicine research track. Dr. Chung's career goal is to become an independent investigator and this plan aims to strengthen her knowledge in pharmacoepidemiology, advanced biostatistics, and clinical pharmacology. These are necessary skills for her transition to become competitive for R01 funding. Vanderbilt University offers her an exceptional environment to develop a successful independent career. The leaders in the Department of Medicine and the Divisions of Rheumatology and Pharmacoepidemiology fully support her plans. Furthermore, Dr. Chung's mentors, Drs. Ray and Stein, are internationally recognized, have a successful track record of mentoring independent investigators, are well-funded, and have committed the time and resources required to train her and foster her career. The K-23 award will allow Dr. Chung to build on her strengths and get the protected time and resources to acquire the skills needed for an independent career in academic rheumatology and pharmacoepidemiology.