Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

精确的英夫利昔单抗暴露和药效学控制可实现小儿克罗恩病的深度缓解

• 批准号: 10631948
• 负责人: Phillip P Minar
• 金额: $ 70.96万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631948
• 关键词: 10 year old; 17 year old; 18 year old; Adrenal Cortex Hormones; Adverse event; Age of Onset; Antibodies; Biological; Biological Markers; Biological Products; Caring; Child; Chronic; Chronic Disease; Clinical; Clinical Trials; Computer software; Crohn' s disease; Data; Development; Disease; Disease remission; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug usage; Effectiveness; Enrollment; Exposure to; Flare; Fostering; Goals; Growth; Hospitalization; Immunosuppressive Agents; Incidence; Individual; Intervention; Intestines; Kidney Transplantation; Label; Leukocyte L1 Antigen Complex; Logistics; Maintenance; Maintenance Therapy; Measures; Modeling; Modification; Monitor; Monoclonal Antibodies; Natural History; North America; Online Systems; Operative Surgical Procedures; Outcome; Patients; Pediatric Crohn' s disease; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physicians; Population; Prednisone; Publishing; Quality of life; Randomized; Randomized, Controlled Trials; Recurrent disease; Regimen; Relapse; Reporting; Risk; Serum; Severities; Statistical Computing; Symptoms; TNF gene; Testing; Therapeutic; Treatment Failure; United States Food and Drug Administration; Validation; adalimumab; arm; clinical decision support; clinical remission; cohort; conventional dosing; dashboard; drug clearance; early adolescence; gastrointestinal symptom; gut inflammation; healing; improved; improved outcome; infliximab; innovation; learning progression; multidisciplinary; neutrophil; novel; novel therapeutics; patient population; peripheral blood; pharmacodynamic biomarker; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pragmatic implementation; randomized, clinical trials; response; support tools; treatment arm; young adult

Project Summary/Abstract Crohn's disease is a chronic illness that results in intestinal inflammation and unwanted gastrointestinal symptoms. The only biologic (monoclonal antibody) approved for moderate to severe Crohn's disease in children (<18 years old) are those that antagonize tumor necrosis factor-alpha (anti-TNF). While there is a high initial response rate to labeled infliximab (anti-TNF) dosing, only half of infliximab exposed patients will achieve clinical remission and less than 40% will achieve endoscopic healing after one year on therapy. Several studies have shown that rates of sustained corticosteroid-free remission are improved when patients receive anti-TNF dose optimizations following reactive or proactive therapeutic drug monitoring. Moreover, anti-TNF dose intensification following pharmacodynamic monitoring has led to improved rates of endoscopic (intestinal) healing. Therefore, given the limited therapeutic options for children with active Crohn's disease, there is a critical unmet need for the development of a data-driven, individualized, and scalable anti-TNF dosing intervention used from drug start and continued throughout therapy to optimize drug exposure and ultimately, improve rates of intestinal healing. Our team has developed a precision dosing strategy that uses an innovative physician decision support dashboard that instantaneously applies pharmacokinetic model-informed precision dosing to generate an individual infliximab dosing regimen starting with induction and targeting phase-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy. The central hypothesis is precision dosing (intervention arm) with infliximab during induction and maintenance will improve rates of deep remission vs. conventional care (pragmatic dosing; control arm). The central hypothesis will be tested with two specific aims. Aim1: Conduct a cluster-randomized (by center) clinical trial to assess rates of deep remission at year1 between Crohn's disease patients receiving infliximab with precision dosing vs. conventional care. Aim2: Refine model- informed precision dosing using a continuous learning approach and identify anti-TNF PK/PD targets from induction to maintenance associated with deep remission. Our approach is conceptually innovative with an emphasis on practical implementation. This is the first clinical trial in children to provide anti-TNF dose optimization during induction to target a specific early (week6) trough concentration while the maintenance regimen is selected by specific treat-to-target pharmacokinetic and pharmacodynamic biomarkers. Additionally, precision dosing regimens are produced with a novel web-based decision support dashboard and the study is being performed within the ImproveCareNow Network to streamline clinical trial logistics. In Aim2, a continuous learning approach will be applied to our published pharmacokinetic model to iteratively refine the model by capturing new real-world data to better describe specific patient populations and further reduce prediction error. The long-term goal is for the precision dosing strategy to generate a paradigm shift as the preferred dosing approach to optimize exposure to all biologics and change the natural history of Crohn's disease.

项目总结/摘要 克罗恩病是一种慢性疾病，导致肠道炎症和不必要的胃肠道炎症。 症状唯一一种获批用于中重度儿童克罗恩病的生物制剂（单克隆抗体） （<18岁）是拮抗肿瘤坏死因子-α（抗TNF）的那些。虽然有很高的初始 英夫利西单抗（抗TNF）标记剂量的反应率，只有一半的英夫利西单抗暴露患者将达到临床 在治疗一年后，不到40%的患者将达到内镜下愈合。几项研究 表明当患者接受抗TNF剂量时， 反应性或主动性治疗药物监测后的优化。此外，抗TNF剂量强化 随后的药效学监测导致内窥镜（肠）愈合率的提高。因此，我们认为， 鉴于活动性克罗恩病儿童的治疗选择有限， 开发一种数据驱动的、个体化的、可扩展的抗TNF给药干预， 并在整个治疗过程中持续进行，以优化药物暴露，并最终提高肠道愈合率。 我们的团队开发了一种精确的给药策略，使用创新的医生决策支持 仪表板，即时应用药代动力学模型通知的精确给药， 个体英夫利西单抗给药方案，从诱导开始，靶向阶段特异性药代动力学， 整个治疗期间的药效学终点。中心假设是精确给药（干预组） 与常规治疗相比，在诱导和维持治疗期间使用英夫利西单抗将提高深度缓解率 （实用剂量;对照组）。中心假设将通过两个具体目标进行检验。目标1：开展 一项评估克罗恩病与非克罗恩病患者第1年深度缓解率的随机分组（按中心）临床试验 接受英夫利西单抗精确给药与常规治疗的疾病患者。目标2：优化模型- 使用持续学习方法进行知情的精确给药，并确定抗TNF PK/PD目标 从诱导期到维持期与深度缓解相关。我们的方法在概念上是创新的 重点是实际执行。这是第一个在儿童中提供抗TNF剂量的临床试验 在诱导期间进行优化，以达到特定的早期（第6周）谷浓度，而维持 根据特定的靶向治疗药代动力学和药效学生物标志物选择治疗方案。此外，本发明还 精确的给药方案是通过一个新的基于网络的决策支持仪表板产生的， 在ImproveCareNow网络内进行，以简化临床试验物流。在Aim 2中，连续 学习方法将应用于我们已发表的药代动力学模型，以通过以下方式迭代完善模型： 捕获新的真实世界数据，以更好地描述特定患者人群，并进一步减少预测误差。 长期目标是精确给药策略作为首选给药产生范式转变 这是一种优化所有生物制剂暴露并改变克罗恩病自然史的方法。