Pharmacokinetic Evaluation to Optimize Infliximab Monotherapy with Personalized Pharmacodynamic Biomarkers

项目总结 个性化炎症性肠病患者的用药剂量和给药间隔 (IBD)将使治疗发生革命性变化。克隆氏病是一种大小不等的复发和缓解性疾病 导致进行性炎症并最终对肠道造成损害的肠道。英夫利昔单抗及类似物 针对克罗恩病患者肿瘤坏死因子-α的药物可以逆转上皮 损害，促进肠道愈合，并防止不必要的克罗恩后遗症，如瘘管或脓肿形成。在……里面 对于患有克罗恩病的儿童和青少年，抗肿瘤坏死因子的使用已经发生了范式转变，以 以提高持续缓解率和扭转增长失败。虽然治疗性药物监测已经 改善英夫利昔单抗的整体耐受性，肠狭窄的终生手术率保持不变 与传统的以重量为基础的剂量停滞不前。成人和儿童的最新药代动力学研究 患有克罗恩病的人发现英夫利昔单抗的清除受到抗原负荷的影响(炎性负荷 肿瘤坏死因子α)、患者体重、血清白蛋白、药物排泄量和免疫原性(药物抗体)。有了这个 英夫利昔单抗清除量有很大的变异性，许多临床医生使用动态给药策略来解释 个人药代动力学，如更频繁的低白蛋白血症给药间隔或增加剂量 5-10 mg/kg，用于重症结肠炎。我们假设，结合了患者特定的特征和新颖的 作为协变量的血液生物标志物将导致更准确地预测英夫利昔单抗的清除量，支持使用 贝叶斯自适应剂量方法在临床实践中的应用。为了检验这一假设，我们提出了一个 严格监测的克罗恩病儿童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样本。在目标1中，我们将开发一种药物动力学 模型基于在诱导过程中影响英夫利昔单抗清除的显著协变量。在目标2中，我们将 基于影响英夫利昔单抗清除量的显著协变量构建药物动力学模型 维修。总之，在药效学的整合之间存在着严重的知识鸿沟。 英夫利昔单抗给药策略的生物标志物，以及治疗时机之间更大的提供者变异性 药物监测和随后的剂量决定。我们的首要目标是将目前的差距降至最低 通过改进、更动态的疾病负担评估和英夫利昔单抗清除，开发一种创新的 用药策略和通过抗肿瘤坏死因子治疗改善患者预后。

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.