Pharmacokinetic Evaluation to Optimize Infliximab Monotherapy with Personalized Pharmacodynamic Biomarkers

项目摘要 炎症性肠病患者个体化用药剂量和给药间隔 (IBD)会彻底改变治疗方法克罗恩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损害肠道。英夫利西单抗和类似药物 针对克罗恩病患者的肿瘤坏死因子-α（TNFα）的药物可以逆转上皮细胞 这些药物可促进肠道损伤，促进肠道愈合，并预防不必要的克罗恩病后遗症，如瘘管或脓肿形成。在 在克罗恩病儿童和青少年中，抗TNF的使用发生了范式转变， 以提高持续缓解率和逆转生长失败。虽然治疗药物监测 改善了英夫利西单抗的整体耐久性，肠狭窄手术的终生率仍然保持不变 传统的基于体重的给药方式停滞不前。成人和儿童的最新药代动力学研究 已经发现英夫利西单抗清除受抗原负荷（炎症负荷， TNFα）、患者体重、血清白蛋白、粪便药物丢失和免疫原性（药物抗体）。与此 英夫利西单抗清除率的显著变化，许多临床医生利用动态给药策略来解释 个体药代动力学，如针对低白蛋白血症的更频繁给药间隔或增加剂量 5 - 10 mg/kg治疗重度结肠炎。我们假设，将患者特异性特征和新的 血液生物标志物作为协变量将导致更准确地预测英夫利西单抗的清除率， 贝叶斯自适应剂量方法的临床实践。为了验证这一假设，我们提出了一个 一项严格监测的儿童克罗恩病队列的药代动力学评价， 英夫利西单抗治疗第一年的纵向生物标本。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西单抗清除率的显著协变量的模型。在目标2中，我们 基于影响英夫利西单抗清除率的显著协变量构建药代动力学模型， 上维护总之，在药效学的整合与药物的整合之间存在着关键的知识差距。 英夫利西单抗给药策略的生物标志物，以及治疗时间之间更大的供应商变异性 药物监测和随后的剂量决定。我们的首要目标是尽量缩小目前的差距 通过改善对疾病负担和英夫利西单抗清除率的更动态评估， 给药策略和改善患者的结果与抗TNF治疗。

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.