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.

项目概要为炎症性肠病患者个体化用药剂量和给药间隔（IBD）将彻底改变克罗恩病的治疗方法，克罗恩病是一种复发性和缓解性的疾病。肠道，导致进行性炎症并最终损害肠道。针对克罗恩病患者肿瘤坏死因子-α (TNFα) 的药物可以逆转上皮细胞损害，促进肠道愈合并预防不必要的克罗恩病后遗症，例如瘘管或脓肿形成。对于患有克罗恩病的儿童和青少年，抗 TNF 药物的使用发生了范式转变，以便提高持续缓解率和逆转生长障碍，同时进行治疗药物监测。提高了英夫利昔单抗的整体耐久性，肠狭窄的终生手术率保持不变最近在成人和儿童中进行的基于体重的传统剂量的药代动力学研究停滞不前。克罗恩病患者发现英夫利昔单抗清除率受到抗原负荷（炎症负荷）的影响 TNFα）、患者体重、血清白蛋白、粪便中药物流失和免疫原性（药物抗体）。英夫利昔单抗清除率存在很大差异，许多顾客利用动态剂量策略来解释个体药代动力学，例如针对低蛋白血症更频繁的给药间隔或增加剂量对于严重结肠炎，我们接受了 5 至 10 毫克/公斤的剂量，并结合了患者的具体特征和新颖性。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，支持使用为了检验这一假设，我们提出了贝叶斯自适应剂量方法在临床实践中的应用。对严格监测的儿科克罗恩病队列进行药代动力学评估，他们提供了英夫利昔单抗治疗第一年的纵向生物样本在目标 1 中，我们将开发药代动力学。基于影响诱导期间英夫利昔单抗清除的显着协变量的模型。基于影响英夫利昔单抗清除期间的显着协变量构建药代动力学模型总之，药效学的整合之间存在着关键的知识差距。英夫利昔单抗剂量策略的生物标志物以及治疗时间之间更大的提供者变异性我们的首要目标是尽量减少目前的差距。通过对疾病负担和英夫利昔单抗清除进行改进、更动态的评估来开发创新的剂量策略并通过抗 TNF 治疗改善患者预后。