POPULATION PHARMACOKINETICS/DYNAMICS--STATISTICAL ISSUES

描述（改编自申请人摘要）：本申请有三个 研究的设计和分析的具体目标 群体药代动力学（PK）和药效学（PD）及其应用 到癌症化疗。 第一个具体的目标提出了扩大对早期贝叶斯分析 作为癌症和白血病组B的一部分收集的血液学数据 （CALGB）I期研究。 特别是，建议开发一个贝叶斯 半参数模型，一个足够灵活，允许异质性和 患者特异性参数分布的过度分散 （随机效应分布），以及非参数回归 患者特异性协变量。 扩展还将包括以下模型 多个纵向结果。 研究人员将重新分析CALGB 第一阶段研究和评估与申请人早期的差异 分析. 第二个具体目标是建立一个预测模型， 血液学毒性对患者特征的影响。 调查人员将 开发贝叶斯分层元模型，并将其应用于来自两个 已完成的CALGB研究：目标一中提到的I期研究和一项大型的 II期乳腺癌患者辅助化疗的I期试验 癌 第三个目标提出了解决优化设计问题的新方法 围绕PK/PD模型构建，诚实地解释了 PK/PD模型中的估计和预测。 特别是 研究人员将应用决策理论的考虑，以制定一个 人群中采集患者血浆时间的合理策略 药代动力学和药效学研究。 他们将评估潜力 通过模拟，与当前有限采样策略相比， 各种假定药代动力学和药效学模型下的研究 在文献中报道。

DESCRIPTION (Adapted from applicant's abstract): This application has three specific aims dealing with the design and analysis of studies into population pharmacokinetics (PK) and pharmacodynamics (PD), with application to cancer chemotherapy. The first specific aim proposes expanding upon an earlier Bayesian analysis of hematology data collected as part of a Cancer and Leukemia Group B (CALGB) Phase I study. In particular, it is proposed to develop a Bayesian semiparametric model, one flexible enough to allow heterogeneity and overdispersion in the distribution of patient-specific parameters (random-effects distribution), as well as non-parametric regression on patient-specific covariates. Extensions will also include models for multiple longitudinal outcomes. The investigators will reanalyze the CALGB Phase I study and evaluate differences from the applicant's earlier analysis. The second specific aim is to develop a predictive model relating hematologic toxicity to patient characteristics. The investigators will develop a Bayesian hierarchical metamodel and apply it to data from two completed CALGB studies: the Phase I study mentioned in aim one and a large Phase I trial of adjuvant chemotherapy for women with stage II breast cancer. The third aim proposes new methodology for solving optimal design problems built around PK/PD models, honestly accounting for uncertainty in the estimation and prediction in the PK/PD models. In particular, the investigators will apply decision-theoretic considerations to develop a rational strategy for picking times to sample patient plasma in population pharmacokinetic and pharmacodynamic studies. They will evaluate potential savings, compared to current limited sampling strategies, via simulation studies under various presumed pharmacokinetic and pharmacodynamic models reported in the literature.