Atypical Antipsychotics: Determinants of Concentration

描述(由申请人提供)：本修订的主要目标 申请(MH64173)，它是抗精神病临床试验的辅助药物 干预有效性(CATIE)的关键是可靠地捕获集中度 抗精神病药物(利培酮、奥氮平、齐拉西酮、 氟奋乃静、奋乃静和氯氮平)使用混合效应群体 药代动力学方法学。群体药动学方法是 非常适合分析来自大型临床的药物浓度数据 干预试验是因为特定患者和总体人群 只需少量血浆样本即可确定药代动力学参数 每个病人。了解药代动力学的可变性对于 合理用药。人口药代动力学方法将允许 与药物暴露有关的可变性程度的测定 在符合以下条件的人群中使用非典型抗精神病药物 照搬临床实践。此外，人口的能力 利用单次给药监测受试者药物暴露的药代动力学模型 本研究将对浓度测量进行评估。人口 药代动力学也被成功地用来确定 药物浓度暴露的可变性。因此，这项辅助研究 将提供一种创新的方法来最佳利用血浆样本 是在凯蒂试验中获得的。CATIE选拔赛将招募多达2250人 患者为每个受试者提供1至6个血药浓度样本 每种药物。一个单独的群体药代动力学模型将是 为包含协变效应的每种药物构建的。特定协变量 将被评估为毒品暴露的潜在贡献者 可变性。要检查的人口统计协变量包括年龄、性别、种族/少数民族 状态和体重指数。其他协变量的潜在影响，如 如之前的药物暴露，伴随药物，吸烟状况， 估计的肾脏清除率和治疗依从性也将被评估。通过 提供“REAL”中非典型抗精神病药物的药代动力学数据 这项研究具有广泛的公共卫生影响，导致 提高对抗精神病药物个体化治疗必要性的认识 适用于患有精神分裂症或阿尔茨海默病的患者。

DESCRIPTION (provided by applicant): The primary goal of this revised application (MH64173), which is ancillary to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), is to reliably capture the concentration exposure of the antipsychotics (risperidone, olanzapine, ziprasidone, fluphenazine, perphenazine, and clozapine) using mixed effect population pharmacokinetic methodologies. The population pharmacokinetic approach is ideally suited for analyzing drug concentration data from large clinical intervention trials because patient-specific as well as overall population pharmacokinetic parameters can be determined using only a few plasma samples per patient. An understanding of pharmacokinetic variability is essential to rational drug prescribing. The population pharmacokinetic approach will permit determination of the extent of variability in drug exposure associated with the use of atypical antipsychotics in large populations under conditions that mirror clinical practice. In addition, the ability of population pharmacokinetic models to capture subjects' drug exposure utilizing single concentration measurements will be assessed in this study. Population pharmacokinetics has also been successfully used to identify sources of variability in drug concentration exposure. Therefore, this ancillary study will provide an innovative way to make optimal use of plasma samples that are being obtained in the CATIE trials. The CATIE trials will recruit up to 2,250 patients providing from 1 to 6 plasma concentration samples per subject for each medication. A separate population pharmacokinetic model will be constructed for each drug incorporating covariate effects. Specific covariates will be then be evaluated as potential contributors to drug exposure variability. Demographic covariates to be examined are age, sex, race/minority status, and body mass index. The potential impact of additional covariates such as prior medication exposure, concomitant medications, smoking status, estimated renal clearance, and treatment adherence will also be assessed. By providing pharmacokinetic data on the atypical antipsychotics under "real world" conditions, this study has broad public health implications, leading to greater awareness of the need to individualize antipsychotics pharmacotherapy for patients suffering from either schizophrenia or Alzheimer's disease.