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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Implications for clinical pharmacodynamic studies of the statistical characterization of an in vitro antiproliferation assay.
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Implications for clinical pharmacodynamic studies of the statistical characterization of an in vitro antiproliferation assay.

机译：体外抗增殖测定的统计表征对临床药效学研究的意义。

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Modeling of nonlinear pharmacodynamic (PD) relationships necessitates the utilization of a weighting function in order to compensate for the heteroscedasticity. The structure of the variance was studied for concentration-effect data generated in an in vitro 96-well plate cell growth inhibition assay, where data are numerous (480 data points per experiment) and replication is easy. From the five candidate models that were considered, the power function S2Y = phi 2Y phi 3, where Y is the sample mean and S2Y is the sample variance, was shown to be the most appropriate to describe the nonuniformity of the variance along the range of measured effect for 253 sets of (Y; S2Y) data. The Hill model was fit to the concentration-effect data with weighted nonlinear regression, where the weights were equal to the reciprocal of the predicted variance. The examination of the distribution of the 253 sets of parameters of the PD model showed that IC50 was lognormally distributed whereas the distribution of gamma was normal. The characterization of the appropriate variance function and concentration-effect function in a simple in vitro experimental setting with a large number of experiments, with each experiment including a large number of data points, will be useful for guiding similar in vitro concentration-effect studies where data are plentiful and for guiding PD modeling in complex clinical settings in which extensive data for model characterization is impossible to obtain.
机译：非线性药效动力学（PD）关系的建模需要利用加权函数来补偿异方差。研究了在体外96孔板细胞生长抑制试验中产生的浓度效应数据的方差结构，该数据众多（每个实验480个数据点）且复制容易。从所考虑的五个候选模型中，幂函数S2Y = phi 2Y phi 3（其中Y是样本均值，S2Y是样本方差）被证明最适合描述沿方差范围的方差的不均匀性。测量253组（Y; S2Y）数据的效果。希尔模型通过加权非线性回归拟合浓度效应数据，其中权重等于预测方差的倒数。对PD模型的253组参数分布的检查表明，IC50呈对数正态分布，而γ呈正态分布。在具有大量实验的简单体外实验环境中表征适当的方差函数和浓度效应函数，每个实验均包含大量数据点，将有助于指导类似的体外浓度效应研究，其中大量的数据可以指导复杂的临床环境中的PD建模，在这些环境中无法获得用于模型表征的大量数据。

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