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

肥胖类风湿和幼年关节炎患者生物制剂的最佳剂量

• 批准号: 10247513
• 负责人: Stephen Joseph Balevic
• 金额: $ 16.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-26 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10247513
• 关键词: Address; Adult; Affect; Agreement; Applications Grants; Arthritis; Biological; Biological Markers; Biological Products; Blood; Child; Childhood; Chronic Childhood Arthritis; Clinic; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Data; Databases; Development Plans; Disease; Doctor of Philosophy; Dose; Drug Kinetics; Drug usage; Effectiveness; Enrollment; Etanercept; Exposure to; Faculty; Failure; Foundations; Frequencies; Future; Goals; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; International; K-Series Research Career Programs; Knowledge; Lead; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Modeling; Non obese; North Carolina; Obesity; Observational Study; Outcome; Pain; Participant; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Physicians; Physiological; Physiology; Population; Protocols documentation; Public Health; Publications; Recording of previous events; Registries; Research; Research Institute; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatology; Safety; Sampling; Science; Scientist; Site; Statistical Data Interpretation; Structure; Supervision; TNF gene; Techniques; Therapeutic; Therapeutic Uses; Training; Treatment Efficacy; Treatment Failure; Universities; adult obesity; career; career development; cytokine; design; disability; dose individualization; drug clearance; drug disposition; educational atmosphere; experience; improved; improved outcome; novel strategies; obese patients; obesity in children; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; prospective; response; skills; standard of care; success; tool; treatment optimization; treatment response; trial design; validation studies; virtual

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.

项目总结/摘要 风湿性关节炎（RA）和幼年特发性关节炎（JIA）是疼痛和残疾的主要原因。而 用生物制剂治疗可以改善结果，但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不良药物反应是否与肥胖有关。 由于生理变化改变药物药代动力学（PK）/药效学（PD）， 炎症状态或两者。Balevic博士建议通过以下方式回应这一需求：1）描述 在RA和JIA中进行的一项前瞻性观察性研究中，肥胖对疾病活动和炎症生物标志物的影响; 2)使用PK/PD建模来研究肥胖对探针生物制剂的药物水平的影响，以及 将药物水平与疾病活动性相关联;以及3）使用PK/PD模型来评估在治疗中的最佳给药策略。 PK/PD临床试验。这个指导职业发展奖将提供一个结构化的学习环境 和专家指导，使博士斯蒂芬Balevic发展为一个独立的调查员和未来 在成人和儿童风湿病治疗领域的领导者。巴列维奇博士的首要任务 职业目标是优化剂量，安全性和药物的有效性，通过整合临床 药理学和药物试验的PK/PD建模。为了实现这一目标，Balevic博士开创了一项事业， 该发展计划利用了他所在的杜克大学与 成人和儿童流变学/杜克临床研究所分部的初级教师，以及 查佩尔山的北卡罗来纳州大学，他正在那里攻读药学博士学位。在 此外，Balevic博士还将通过一个独特的 与FDA签订培训协议。他对K23计划的短期目标是：1）获得先进的 PK/PD建模的知识和技能; 2）发展专业技能和技术，以领导临床 试验团队;以及3）生成临界质量的初步数据和出版物，以支持R 01赠款 应用程序.导师团队有着以往的合作历史，有着成功的导师记录 并在药物反应、肥胖、PK/PD的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。在成功完成这项提案后，Balevic博士将获得 在促进成人和儿童安全有效地使用药物方面追求终身职业的必要技能 患有风湿病