Pharmacokinetic Evaluation to Optimize Infliximab Monotherapy with Personalized Pharmacodynamic Biomarkers

使用个性化药效生物标志物优化英夫利昔单抗单一疗法的药代动力学评估

基本信息

批准号：
9768437
负责人：
Phillip P Minar
金额：
$ 11.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768437
关键词：
Abdominal Pain Abscess Adolescent Adult Affect Aminoglycoside Antibiotics Anti-Tumor Necrosis Factor Therapy Antibodies Antigens Bayesian Modeling Biological Assay Biological Markers Blood Blood Tests Characteristics Child Childhood Chronic Clinical Clinical Decision Support Systems Colitis Complex Computer software Concentration measurement Crohn&apos s disease Custom Data Development Diarrhea Disease Disease remission Dose Down-Regulation Drug Exposure Drug Kinetics Drug Monitoring Epithelial Evaluation Failure Fistula Friends Funding Goals Grant Growth Hypoalbuminemia Individual Inflammation Inflammatory Inflammatory Bowel Diseases Infusion procedures Intestines Intuition Investigation Knowledge Large Intestine Maintenance Malignant Neoplasms Modeling Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Operative Surgical Procedures Patient-Focused Outcomes Patients Pediatric Crohn&apos s disease Pediatrics Pharmaceutical Preparations Pharmacodynamics Phase Phenytoin Plasma Proteins Population Process Proteomics Provider Randomized Controlled Clinical Trials Randomized Controlled Trials Regimen Relapse Reporting Scheme Schools Secondary to Selection for Treatments Serum Albumin Small Intestines Source System TNF gene Testing Therapeutic Time Treatment Efficacy Treatment Failure Ulcerative Colitis United States Weight Work base burden of illness clinical decision support clinical practice clinical remission cohort dashboard dose individualization effective therapy healing immunogenicity improved individual patient infliximab innovation neutrophil novel novel marker pharmacodynamic biomarker pharmacodynamic model pharmacokinetic model prevent primary endpoint receptor response secondary endpoint specific biomarkers trial comparing user-friendly

项目摘要

PROJECT SUMMARY Personalizing medication dose and dosing intervals for the individual patient with inflammatory bowel disease (IBD) would revolutionize treatment. Crohn’s disease is a relapsing and remitting disease of the large and small intestines that results in progressive inflammation and eventual damage to the bowel. Infliximab, and similar medications that target tumor necrosis factor-alpha (TNFα) in Crohn’s disease patients, can reverse epithelial damage, promote bowel healing and prevent unwanted Crohn’s sequela such as fistula or abscess formation. In children and young adolescents with Crohn’s disease, there has been a paradigm shift in anti-TNF use in order to improve rates of sustained remission and reverse growth failure. While therapeutic drug monitoring has improved the overall durability of infliximab, lifetime rates of surgery for intestinal strictures have remained stagnant with conventional, weight-based dosing. More recent pharmacokinetic studies in adults and children with Crohn’s disease have found infliximab clearance is affected by antigen load (inflammatory burden with TNFα), patient weight, serum albumin, fecal loss of drug and immunogenicity (antibodies to drug). With this substantial variability with infliximab clearance, many clinicians utilize dynamic dosing strategies to account for individual pharmacokinetics such as more frequent dosing intervals for hypoalbuminemia or increasing the dose from 5 to 10 mg/kg for severe colitis. We hypothesize that incorporating patient-specific characteristics and novel blood biomarkers as covariates will result in more accurate prediction of infliximab clearance supporting the use of a Bayesian adaptive-dosing approach in clinical practice. To test this hypothesis, we have proposed a pharmacokinetic evaluation of a rigorously monitored pediatric Crohn disease cohort who have provided longitudinal biospecimens during the first year of infliximab therapy. In Aim 1, we will develop a pharmacokinetic model based on significant covariates that influence infliximab clearance during induction. In Aim 2, we will construct a pharmacokinetic model based on significant covariates that influence infliximab clearance during maintenance. In conclusion, there is a critical knowledge gap between the integration of pharmacodynamic biomarkers with infliximab dosing strategies and even greater provider variability between timing of therapeutic drug monitoring and the subsequent dosing decisions. Our overarching goal is to minimize these current gaps with improved, more dynamic assessments of disease burden and infliximab clearance to develop an innovative dosing strategy and improve patient outcomes with anti-TNF therapies.

项目摘要个性化药物剂量和给人以炎症性肠病患者的剂量间隔（IBD）将彻底改变治疗。克罗恩病是大小不一的传递和恢复疾病导致肠道感染和事件损害肠道的肠道。英夫利昔单抗，类似靶向靶向肿瘤坏死因子 - α（TNFα）的药物，在克罗恩病患者中可以逆转上皮损害，促进肠道愈合并防止不必要的克罗恩续集，例如瘘管或脓肿形成。克罗恩病的儿童和年轻青少年，反TNF的使用范式转移了提高持续缓解和反向生长失败的速度。而治疗药物监测有提高了英夫利昔单抗的整体耐用性，肠道狭窄的手术寿命率仍然存在停滞不前，基于体重的剂量。最新的成人和儿童的药代动力学研究由于克罗恩病的发现，英夫利昔单抗的清除受抗原负荷影响（炎症性灼伤与 TNFα），患者体重，血清白蛋白，药物的粪便丧失和免疫原性（对药物的抗体）。与此英夫利昔单抗清除率很大的可变性，许多临床医生利用动态剂量策略来解释单个药代动力学，例如低钙血症的更频繁的给药间隔或增加剂量严重结肠炎的5至10 mg/kg。我们假设结合患者特异性特征和新颖血液生物标志物作为协变量将导致更准确地预测英夫利昔单抗清除率，以支持该使用在临床实践中的贝叶斯自适应方法。为了检验这一假设，我们提出了对已提供的严格监测的儿科克罗恩病队列的药代动力学评估英夫利昔单抗治疗第一年的纵向生物测量。在AIM 1中，我们将开发一种药代动力学基于重要的协变量的模型，这些协变量会影响诱导过程中英夫利昔单抗的清除率。在AIM 2中，我们将基于重要的协变量来构建药代动力学模型维护。总之，药效学的整合之间存在关键的知识差距具有英夫利昔单抗剂量策略的生物标志物，治疗时间之间的差异更大药物监测和随后的给药决定。我们的总体目标是最大程度地减少这些当前差距随着对疾病伯恩和英夫利昔单抗清除的改进，更具动态的评估，以发展创新给药策略并通过抗TNF疗法改善患者的结局。