Optimal Dosing for Biologic Agents in Obese Patients with Rheumatoid and Juvenile Arthritis

项目摘要/摘要 类风湿性关节炎(RA)和青少年特发性关节炎(JIA)是导致疼痛和残疾的主要原因。而当 使用生物制剂治疗可能会改善结果，治疗失败在肥胖患者中很常见。 尽管治疗失败的影响很大，但目前尚不清楚肥胖症的药物反应差是否 由于生理变化改变了药物的药代动力学(PK)/药效学(PD)，潜在的 炎症状态，或两者兼而有之。巴列维奇博士建议通过以下方式来回应这一需求：1)描述 在RA和JIA的一项前瞻性观察研究中，肥胖对疾病活动性和炎症生物标志物的影响； 2)使用PK/PD模型研究肥胖对探针生物制剂药物浓度的影响，以及 将药物水平与疾病活动性联系起来；以及3)使用PK/PD模型来评估在 PK/PD临床试验。这项指导职业发展奖将提供一个有组织的学习环境 和专家指导，使斯蒂芬·巴列维奇博士能够发展成为一名独立的研究员和未来 风湿病成人和儿童治疗领域的领导者。巴列维奇博士最重要的是 职业目标是通过整合临床治疗来优化药物的剂量、安全性和有效性 药物试验的药理学和PK/PD模型。为了实现这一目标，巴列维奇博士开创了一项事业 发展计划，利用杜克大学和他所在的杜克大学之间的长期合作 成人和儿科风湿病/杜克临床研究所初级教员，以及 他在北卡罗来纳大学教堂山分校攻读药学博士学位。在……里面 此外，巴列维奇博士将通过一个独特的 与食品和药物管理局签订了培训协议。他对K23项目的短期目标是：1)获得先进的 PK/PD建模的知识和技能；2)培养领导临床的专业技能和技能 试验团队；以及3)生成大量的初步数据和出版物以支持R01赠款 申请。导师团队有以前合作的历史，有成功的导师记录 初级教员，在药物反应、肥胖、PK/PD生物标志物方面拥有国际公认的专业知识 建模和临床试验。在成功完成这项提议后，巴列维奇博士将获得 在成人和儿童中推广安全和有效使用药物的终身职业所需的技能 患有风湿病。

PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) and Juvenile Idiopathic Arthritis (JIA) are leading causes of pain and disability. While treatment with biologic agents may improve outcomes, treatment failure is common in patients who are obese. Despite the significant impact of treatment failure, it is currently unknown if the poor drug response in obesity is due to physiologic changes altering drug pharmacokinetics (PK)/Pharmacodynamics (PD), the underlying inflammatory state, or both. Dr. Balevic proposes to respond to this need by 1) characterizing the effects of obesity on disease activity and biomarkers of inflammation in a prospective observational study in RA and JIA; 2) using PK/PD modeling to investigate the effect of obesity on drug levels for a probe biologic agent, and relate drug levels to disease activity; and 3) using the PK/PD model to evaluate an optimal dosing strategy in a PK/PD clinical trial. This Mentored Career Development Award will provide a structured learning environment and expert mentorship to enable Dr. Stephen Balevic to develop as an independent investigator and future leader in the field of therapeutics for adults and children with rheumatic disease. Dr. Balevic’s overarching career goal is to optimize the dosing, safety, and effectiveness of medications by integrating clinical pharmacology and PK/PD modeling with drug trials. To achieve this goal, Dr. Balevic created a career development plan that capitalizes on the longstanding collaboration between Duke University, where he is junior faculty in the Divisions of Adult and Pediatric Rheumatology/Duke Clinical Research Institute, and the University of North Carolina at Chapel Hill, where he is pursuing a PhD in Pharmaceutical Sciences. In addition, Dr. Balevic will enhance his training in the regulatory conduct of clinical trials through a unique training agreement with the FDA. His short-term goals for the K23 program are: 1) to acquire advanced knowledge and skills in PK/PD modeling; 2) develop the professional skills and techniques to lead a clinical trials team; and 3) generate a critical mass of preliminary data and publications to support an R01 grant application. The mentorship team has a history of prior collaboration, a proven record of successful mentorship of junior faculty, and has internationally recognized expertise in biomarkers of drug response, obesity, PK/PD modeling, and clinical trials. Upon successful completion of this proposal, Dr. Balevic will have acquired the necessary skillset to pursue a lifelong career in promoting safe and effective use of drugs in adults and children with rheumatic disease.