Atypical Antipsychotics: Determinants of Concentration

描述（由申请人提供）：本修订版的主要目标 申请（MH 64173），作为临床抗精神病药物试验的辅助 干预有效性（CATIE）是可靠地捕捉浓度 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）使用混合效应人群 药代动力学方法。群体药代动力学方法是 非常适合分析来自大型临床试验的药物浓度数据， 干预试验，因为患者特异性和总体人群 药代动力学参数可以仅使用少量血浆样品来确定 每名患者。了解药代动力学变异性对于 合理用药群体药代动力学方法将允许 确定与药物暴露相关的变异程度， 非典型抗精神病药在大规模人群中的使用， 反映临床实践。此外，人口的能力 利用单次给药采集受试者药物暴露的药代动力学模型 在本研究中将评估浓度测量。人口 药代动力学也已成功地用于确定 药物浓度暴露的变异性。因此，本辅助研究 将提供一种创新的方式，使血浆样本的最佳利用， 在CATIE试验中获得。CATIE试验将招募多达2，250人 患者提供每例受试者1 - 6份血浆浓度样本， 每一种药将建立单独的群体药代动力学模型， 构建了每种药物的协变量效应。特定协变量 然后将被评价为药物暴露的潜在贡献者 可变性待检查的人口统计学协变量为年龄、性别、种族/少数民族 状态和体重指数。其他协变量（如 既往药物暴露、合并用药、吸烟状态， 还将评估估计的肾清除率和治疗依从性。通过 提供“真实的”下非典型抗精神病药的药代动力学数据 “世界”条件下，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治疗个体化必要性的认识 治疗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.