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首页> 外文期刊>Journal of applied statistics >Optimal Parametric Design with Applications to Pharmacokinetic and Pharmacodynamic Trials
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Optimal Parametric Design with Applications to Pharmacokinetic and Pharmacodynamic Trials

机译：优化参数设计及其在药代动力学和药效学试验中的应用

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摘要

This paper considers optimal parametric designs, i.e. designs represented by probability measures determined by a set of parameters, for nonlinear models and illustrates their use in designs for pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) trials. For some practical problems, such as designs for modelling PK/PD relationship, this is often the only feasible type of design, as the design points follow a PK model and cannot be directly controlled. Even for ordinary design problems the parametric designs have some advantages over the traditional designs, which often have too few design points for model checking and may not be robust to model and parameter misspecifications. We first describe methods and algorithms to construct the parametric design for ordinary nonlinear design problems and show that the parametric designs are robust to parameter misspecification and have good power for model discrimination. Then we extend this design method to construct optimal repeated measurement designs for nonlinear mixed models. We also use this parametric design for modelling a PK/PD relationship and propose a simulation based algorithm. The application of parametric designs is illustrated with a three-parameter open one-compartment PK model for the ordinary design and repeated measurement design, and an Emax model for the phamacokinetic/pharmacodynamic trial design.
机译：本文考虑了非线性模型的最佳参数设计，即以一组参数确定的概率测度表示的设计，并说明了它们在药代动力学（PK）和药代动力学/药效学（PK / PD）试验设计中的使用。对于某些实际问题，例如用于对PK / PD关系进行建模的设计，这通常是唯一可行的设计类型，因为设计点遵循PK模型且无法直接控制。即使对于普通的设计问题，参数设计也比传统设计有一些优势，传统设计通常没有太多的设计点来进行模型检查，并且对于模型和参数的错误指定可能不那么可靠。我们首先描述了用于构造普通非线性设计问题的参数设计的方法和算法，并表明参数设计对参数错误指定具有鲁棒性，并具有很好的模型判别能力。然后，我们将这种设计方法扩展到构造非线性混合模型的最佳重复测量设计。我们还使用此参数设计来建模PK / PD关系，并提出基于仿真的算法。通过三参数开放式一室PK模型（用于普通设计和重复测量设计）和Emax模型（用于动力学/药效学试验设计）来说明参数设计的应用。

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