Pharmacokinetic Pharmacodynamic Studies of Methylphenidate Extended Release Products in Pediatric Attention Deficit Hyperactivity Disorder

哌甲酯缓释产品治疗小儿注意力缺陷多动障碍的药代动力学药效学研究

• 批准号: 9743622
• 负责人: Thomas J Spencer
• 金额: $ 25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9743622
• 关键词: Pharmacokinetic; Pharmacodynamic; Studies; Methylphenidate; Extended

Pharmacokinetic/Pharmacodynamic (PK/PD) Studies of Methylphenidate Extended Release Products in Pediatric Attention Deficit Hyperactivity Disorder (ADHD) (U01) Summary/Abstract We propose to conduct a prospective pharmacokinetic (PK)/pharmacodynamic (PD) study of long acting methylphenidate (MPH) formulations in pediatric ADHD patients to examine novel PK parameters beyond AUC and Cmax, traditionally used to determine generic equivalency. Long acting MPH formulations considered equivalent by PK (AUC and Cmax) were shown to be significantly different in PD for onset, midday effectiveness as well as offset. To address these limitations, we propose to test the PK/PD relationship of MPH in three distinct PK profiles (shapes): 1) gradual onset with ascending kinetics (OROS); 2) rapid onset with biphasic pulse delivery kinetics (two peaks and troughs; Ritalin LA); 3) rapid onset with one pulse delivery kinetics (one peak; Quillivant XR). In each model, we will separately assess the initial (onset), middle and terminal (offset) portions of the PK/PD relationship as assessed through an analogue laboratory classroom methodology. A disease–drug–trial model paradigm will be applied to the data to integrate MPH PK findings, covariates, time course of clinical outcomes, placebo effects, drug's pharmacologic effects, and trial execution characteristics. This approach will provide guidance for the evaluation of the impact of different concentration- time profiles on the PD effect of MPH extended release products (1). A population PK/PD model will be developed using individual observations collected in the target pediatric population to explain the drug response accounting for the placebo effect and for the time varying response of MPH (tachyphylaxis). A previously developed PK/PD model (2) was implemented using a meta-analytic approach using mean data extracted from published papers. This model was able to predict pediatric PD [both math tests (PERMP) and behavioral ratings (SKAMP)] from adult PK data. To improve upon limitations of this model, we propose to generalize the model by using pediatric PK instead of adult PK and, most importantly, to use individual PK and PD measurements rather than relying on mean observations as well as to separately address onset, midday and offset. Our overarching objective is to provide a validated model appropriate for predicting, with a known uncertainty level, the impact of a given PK profile on the therapeutic equivalence of MPH extended release products. The findings from this proposed novel PK/PD study will help establish scientific and regulatory standards for assuring therapeutic equivalence of generic methylphenidate extended release products.

哌醋甲酯缓释产品的药代动力学/药效学 (PK/PD) 研究 儿童注意力缺陷多动障碍 (ADHD) (U01) 摘要/摘要 我们建议对长效药物进行前瞻性药代动力学（PK）/药效学（PD）研究 哌醋甲酯 (MPH) 制剂用于儿科 ADHD 患者，以检查 AUC 之外的新 PK 参数 和 Cmax，传统上用于确定所考虑的长效 MPH 制剂。 PK 等效值（AUC 和 Cmax）在起病、中午的 PD 中表现出显着差异 为了解决这些限制，我们建议测试 PK/PD 关系。 MPH 具有三种不同的 PK 曲线（形状）：1）渐进式上升动力学 (OROS)；2) 快速起效； 采用双相脉冲传递动力学（两个峰和谷；利他林 LA）；3) 一次脉冲传递快速起效； 动力学（一个峰；Quillivant XR）在每个模型中，我们将分别评估初始（开始）、中间和 通过模拟实验室教室评估的 PK/PD 关系的终端（偏移）部分 疾病-药物-试验模型范式将应用于数据以整合 MPH PK 结果， 协变量、临床结果的时间进程、安慰剂效应、药物的药理作用和试验执行 该方法将为评估不同浓度的影响提供指导。 MPH 缓释产品的 PD 效果的时间曲线 (1) 为群体 PK/PD 模型。 使用在目标儿科人群中收集的个人观察结果来解释该药物 解释了安慰剂效应和 MPH A 的随时间变化的反应（快速耐受）。 先前开发的 PK/PD 模型 (2) 是使用平均数据的荟萃分析方法实现的 该模型能够预测儿科 PD [数学测试 (PERMP) 和 来自成人 PK 数据的行为评级（SKAMP）] 为了改进该模型的局限性，我们建议 通过使用儿童 PK 而不是成人 PK 来推广模型，最重要的是，使用个体 PK 和 PD 测量，而不是依赖平均观测值以及单独解决发病问题， 我们的首要目标是提供一个适合预测的经过验证的模型，并具有 已知的不确定性水平，给定 PK 曲线对 MPH 延长治疗等效性的影响 这项拟议的新颖 PK/PD 研究的结果将有助于建立科学和合理的产品。 确保仿制药哌醋甲酯缓释治疗等效性的监管标准 产品。