RISPERIDONE PHARMACOKINETICS IN CHILDREN WITH PDD

描述（由申请人提供）：广泛性发育障碍（PDD）是 一种极度衰弱的儿童行为障碍， 包括孤独症，并且缺乏有效的治疗。抗精神病药物使用 即使在2岁的儿童中，PDD也很高。PDD人口出现 特别易受伤害，并面临更大的严重后遗症风险 包括锥体外系副作用（EPS）和迟发性运动障碍。非典型 抗精神病药利培酮（RIS）现在用于87%的儿科病例，但 在这一脆弱人群中缺乏药代动力学（PK）和安全性数据。 我们的实验室最近探索了 RIS和EPS的个体间代谢。最近的证据表明， RIS的主要活性代谢产物9-羟基利培酮（9-OH-RIS）存在于 对映体形式具有潜在不同的毒性特征。这种代谢 这一发现，加上缺乏PDD儿童的基本PK信息， 表明需要进一步研究以促进更好的剂量滴定和安全性， RIS的临床应用我们的研究计划是：（1）适应和建立 方法足以进行儿科采样;（2）证明RIS的可行性， 儿科PDD患者样品中9-OH-RIS对映体的测定;（3） 收集足以提供参数估计值的初步群体PK数据 允许未来在患有以下疾病的儿童中进行完整的群体PK表征 PDD，并探索EPS不良事件数据与RIS之间的关系 代谢/消除。我们提出了一个协作的多中心方法 利用两个NIH支持的儿科 药理学网络;即儿科药理学研究单位（PPRU） (lead辛辛那提儿童医院）和儿科研究中心 精神药理学（RUPP）网络（牵头机构俄亥俄州）。这一战略将 依靠每个网络的独特优势和专业知识， 开发创新技术，并将其应用于弱势群体， 实现公共卫生效益最大化。RUPP网络能够访问PDD 患者和优化临床采样，而PPRU网络具有专业知识， 微量测定开发和进入GLP认证实验室（路易斯安那州 大学）以及群体PK专业知识（辛辛那提和圣地亚哥）。 具体来说，我们计划进行一项群体PK研究， RIS的浓度-时间曲线， 密集的数据，通过药物的早期和晚期的吸收阶段水平 消除，稀疏采样策略。人口办法将 允许分析来自正在进行的临床试验以及研究的数据 专为PK评价设计。RIS和9-OH-RIS对映体 将使用新的低容量高灵敏度测定法测定浓度。 同时，我们将调查RIS的治疗血浆浓度， 9-OH-RIS对映体，表征药效学RIS和9-OH-RIS对映体 (e.g. EPS），并获得安全性/不良事件数据。

DESCRIPTION (provided by applicant): Pervasive Developmental Disorder (PDD) is a category of extremely debilitating behavioral disorder of childhood which includes autism, and for whom efficacious therapy is lacking. Neuroleptic use in PDD is high even in children as young as 2 years. The PDD population appears to be particularly vulnerable and at increased risk of serious sequelae including extrapyramidal side effects (EPS) and tardive dyskinesia. An atypical neuroleptic risperidone (RIS) is now used in 87 percent of pediatric cases, but pharmacokinetic (PK) and safety data are lacking in this vulnerable population. Our laboratory has recently explored the relationship between the inter-individual metabolism of RIS and EPS. Recent evidence suggests that the major active metabolite of RIS, 9-hydroxyrisperidone (9-OH-RIS) is present in enantiomeric forms with potentially differing toxic profiles. This metabolic finding, coupled with the lack of basic PK information in children with PDD, suggests further study is needed to promote better dose titration and safety in the clinical use of RIS. Our research plan is to: (1) adapt and establish assay methodology sufficient for pediatric sampling; (2) prove feasibility of RIS and 9-OH-RIS enantiomers determination in samples from pediatric PDD patients; (3) gather preliminary population PK data sufficient to provide parameter estimates to allow future full population PK characterization in children suffering from PDD, and explore the relationship between EPS adverse event data and RIS metabolism/ elimination. We propose a collaborative multi-center approach utilizing the complementary strengths of two NIH supported Pediatric Pharmacology Networks; i.e. the Pediatric Pharmacology Research Unit (PPRU) (lead site Cincinnati Children's) and the Research Units of Pediatric Psychopharmacology (RUPP) networks (lead site Ohio State). This strategy will rely on the unique strengths and expertise of each network to collaboratively produce innovative technology and apply it to a vulnerable population to achieve maximum public health benefit. The RUPP network is able to access PDD patients and optimize clinical sampling while the PPRU network has expertise in micro-assay development and access to a GLP certified lab (Louisiana State University) as well as population PK expertise (Cincinnati and San Diego). Specifically, we plan a population PK study in which we will determine drug concentration-time profiles of RIS by integrating information from relatively dense data, absorption phase levels through the early and late hours of drug elimination, with a sparse sampling strategy. The population approach will allow the analysis of data from ongoing clinical trials as well as from a study specifically designed for PK evaluation. RIS and 9-OH-RIS enantiomeric concentrations will be determined with a new low volume high sensitivity assay. Simultaneously we will survey therapeutic plasma concentrations of RIS and 9-OH-RIS enantiomers, characterize pharmacodynamic RIS and 9-OH-RIS enantiomers (e.g. EPS), and obtain safety/adverse event data.