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残疾的主要原因，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具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相互作用。特别重要的是由CYP 3A介导的药物相互作用，CYP 3A是细胞色素P-450（CYP）成员，参与所有药物的60%以上的代谢。该提案将定义CYP 3A介导的药物相互作用的风险及其作为解释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入组者的大型数据库，这些研究将收集接受选定的具有巨大毒性潜力的CYP 3A底物药物的队列：（1）阿片类药物羟考酮和芬太尼和（2）秋水仙碱使用者，并定义与CYP 3A抑制剂联合治疗相关的临床重要结局的风险。更好地了解这些风险将导致从业人员避免合并使用相互作用的药物，导致临床显着的毒性。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。她在范德比尔特获得了公共卫生硕士学位，并完成了由T-32赠款资助的临床药理学额外培训。同时，她完成了美国内科医学委员会研究轨道下的风湿病学奖学金。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，先进的生物统计学和临床药理学方面的知识。这些都是必要的技能，她的过渡成为竞争力的R 01资金。范德比尔特大学为她提供了一个特殊的环境，以发展一个成功的独立职业生涯。医学系、流变学和药物流行病学系的领导完全支持她的计划。此外，钟博士的导师雷博士和斯坦博士是国际公认的，在指导独立调查人员方面有着成功的记录，资金充足，并投入了培训她和促进她的职业生涯所需的时间和资源。K-23奖将使Chung博士能够发挥她的优势，并获得受保护的时间和资源，以获得在学术流变学和药物流行病学方面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.