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

哌甲酯缓释片的药代动力学/药效学(PK/PD)研究 儿童注意缺陷多动障碍(ADHD)(U01) 摘要/摘要 我们建议进行一项长效的前瞻性药代动力学(PK)/药效学(PD)研究 在儿童ADHD患者中使用哌醋甲酯(MPH)制剂检查AUC以外的新PK参数 和Cmax，传统上用于确定类属等价性。考虑长效MPH配方 PK等效值(AUC和Cmax)在帕金森病的发病、中午和中午显示出显著差异 有效性和抵消性。为了解决这些限制，我们建议测试PK/PD关系 MPH有三种不同的PK曲线(形状)：1)渐进性起病伴上升动力学(OROS)；2)快速起病 具有双相脉冲给药动力学(双峰和双谷；利他林LA)；3)一次脉冲给药快速起效 动力学(单峰；Quillivant XR)。在每个模型中，我们将分别评估初始(开始)、中期和 通过模拟实验室教室评估的PK/PD关系的终端(补偿)部分 方法论。疾病-药物-试验模型范式将被应用于数据以整合MPH PK发现， 协变量、临床结果的时间进程、安慰剂效应、药物的药理效应和试验执行 特点。这种方法将为评估不同浓度的影响提供指导- MPH缓释剂释药效应的时间分布(1)。人口PK/PD模型将是 利用在目标儿科人群中收集的个人观察来解释药物 反应解释了安慰剂效应和MPH的时变反应(快速反应)。一个 之前开发的PK/PD模型(2)使用元分析方法使用平均数据来实现 摘自已发表的论文。该模型能够预测儿童PD[数学考试(PERMP)和 行为评级(SKAMP)]来自成人PK数据。为了改善这一模式的局限性，我们建议 推广使用儿童PK而不是成人PK，最重要的是使用个人PK 和PD测量，而不是依赖于平均观测以及单独寻址起始点， 正午和偏移量。我们的首要目标是提供一个适用于预测的经过验证的模型，具有 已知的不确定性水平，给定的PK配置文件对MPH治疗等效性的影响延长 发布产品。这项拟议的新的PK/PD研究的结果将有助于建立科学和 确保非专利哌酸甲酯缓释剂治疗等效性的管理标准 产品。

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.