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.

哌醋甲酯缓释制剂的药代动力学/药效学（PK/PD）研究 儿童注意力缺陷多动障碍（ADHD）（U 01） 摘要/摘要 我们建议进行一项前瞻性药代动力学（PK）/药效学（PD）研究， 哌甲酯（MPH）制剂用于儿童ADHD患者，以检查AUC以外的新PK参数 和Cmax，传统上用于确定类属等效性。长效MPH制剂 PK等效值（AUC和Cmax）在PD中显示出显著性差异， 有效性和抵消。为了解决这些局限性，我们建议测试以下药物的PK/PD关系： MPH具有三种不同的PK曲线（形状）：1）逐渐起效，动力学上升（OROS）; 2）快速起效 具有双相脉冲输送动力学（两个峰和谷;利他林LA）; 3）具有一个脉冲输送的快速起效 动力学（一个峰; Quillivant XR）。在每个模型中，我们将分别评估初始（发作）、中期和 通过模拟实验室教室评估的PK/PD关系的终末（偏移）部分 方法论疾病-药物-试验模型范例将应用于数据，以整合MPH PK结果， 协变量、临床结局的时间进程、安慰剂效应、药物药理学效应和试验执行 特色这种方法将为评价不同浓度的影响提供指导- MPH缓释产品PD效应的时间曲线（1）。将建立群体PK/PD模型 使用在目标儿科人群中收集的个体观察结果来解释药物 解释安慰剂效应和MPH（快速耐受）随时间变化的反应。一 使用平均数据，采用荟萃分析方法实施先前开发的PK/PD模型（2） 摘自已发表的论文。该模型能够预测儿童PD [数学测试（PERMP）和 行为评级（SKAMP）]。为了改善这种模式的局限性，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，而不是依赖于平均观察以及单独解决发作， 中午和抵消。我们的首要目标是提供一个经过验证的模型，适用于预测， 已知不确定性水平，给定PK特征对MPH治疗等效性的影响扩展 释放产品。这项拟议的新型PK/PD研究的结果将有助于建立科学和 用于确保通用哌甲酯缓释剂的治疗等效性的监管标准 产品.